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WO2014197854A1 - Nouveaux lieurs pour conjugués anticorps-médicament et composés connexes, compositions, et procédés d'utilisation - Google Patents

Nouveaux lieurs pour conjugués anticorps-médicament et composés connexes, compositions, et procédés d'utilisation Download PDF

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Publication number
WO2014197854A1
WO2014197854A1 PCT/US2014/041399 US2014041399W WO2014197854A1 WO 2014197854 A1 WO2014197854 A1 WO 2014197854A1 US 2014041399 W US2014041399 W US 2014041399W WO 2014197854 A1 WO2014197854 A1 WO 2014197854A1
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WIPO (PCT)
Prior art keywords
alkyl
group
independently
linker
antibody
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PCT/US2014/041399
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English (en)
Inventor
David Jackson
Edward Ha
Original Assignee
Igenica Biotherapeutics, Inc.
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Publication date
Priority claimed from PCT/US2013/064147 external-priority patent/WO2014059028A1/fr
Application filed by Igenica Biotherapeutics, Inc. filed Critical Igenica Biotherapeutics, Inc.
Priority to US14/895,893 priority Critical patent/US11229711B2/en
Publication of WO2014197854A1 publication Critical patent/WO2014197854A1/fr
Priority to US17/545,562 priority patent/US20230109312A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A61K47/6819—Plant toxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell

Definitions

  • This invention relates to novel linkers for antibody-drug conjugates (ADCs) and related compounds, such as linkers used to make them, and intermediates in their synthesis; compositions; and methods, including methods of treating cancers.
  • ADCs antibody-drug conjugates
  • Cancer is the second most prevalent cause of death in the U.S, yet there are few effective treatment options beyond surgical resection.
  • the use of monoclonal antibodies targeting antigens present on the cancer cells has become common.
  • alemtuzumab CAMPATH ®
  • bevacizumab AVASTIN®
  • cetuximab ERBITUX ®
  • a chimeric anti- epidermal growth factor antibody used in colorectal cancer, head and neck cancer, and squamous cell carcinoma
  • ipilimumab YERVOY ®
  • a human anti-CTLA-4 antibody used in melanoma
  • ofatumumab ARZERRA ®
  • a human anti-CD20 antibody used in chronic lymphocytic leukemia panitumumab (VECTIBIX ® ), a human anti-epidermal growth factor receptor antibody used in colorectal cancer
  • rituximab a chimeric anti-CD20 antibody used in non-
  • BEXXAR ® a murine anti-CD20 antibody used in non-Hodgkin lymphoma
  • trastuzumab HERCEPTIN ®
  • HERCEPTIN ® a humanized anti-HER2 antibody used in breast cancer. While these antibodies have proven useful in the treatments of the cancers for which they are indicated, they are rarely curative as single agents, and are generally used in combination with standard chemotherapy for the cancer.
  • trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor2 protein, HER2 (ErbB2) (Coussens et al., Science 1985, 230, 1132-9; Salmon et al., Science 1989, 244, 707-12), thereby inhibiting the growth of HER2-positive cancerous cells.
  • HER2 human epidermal growth factor receptor2 protein
  • HERCEPTIN is useful in treating patients with HER2- overexpressing breast cancers that have received extensive prior anti-cancer therapy, some patients in this population fail to respond or respond only poorly to HERCEPTIN treatment. Therefore, there is a significant clinical need for developing further HER2- directed cancer therapies for those patients with HER2-overexpressing tumors or other diseases associated with HER2 expression that do not respond, or respond poorly, to HERCEPTIN treatment.
  • ADCs Antibody drug conjugates
  • a rapidly growing class of targeted therapeutics represent a promising new approach toward improving both the selectivity and the cytotoxic activity of cancer drugs. See, for example, Trail et al., “Monoclonal antibody drug immunoconjugates for targeted treatment of cancer", Cancer Immunol. Immunother. 2003, 52, 328-337; and Chari, “Targeted Cancer Therapy: Conferring Specificity to Cytotoxic Drugs", Acc. Chem. Res., 2008, 41(1), 98-107.
  • ADCs have three components: (1) a monoclonal antibody conjugated through a (2) linker to a (3) cytotoxin.
  • the cytotoxins are attached to either lysine or cysteine sidechains on the antibody through linkers that react selectively with primary amines on lysine or with sulfhydryl groups on cysteine.
  • the maximum number of linkers/drugs that can be conjugated depends on the number of reactive amino or sulfhydryl groups that are present on the antibody.
  • a typical antibody contains up to 90 lysines as potential conjugation sites; however, the optimal number of cytotoxins per antibody for most ADCs is typically between 2 and 4 due to aggregation of ADCs with higher numbers of cytotoxins.
  • lysine linked ADCs currently in clinical development are heterogeneous mixtures that contain from 0 to 10 cytotoxins per antibody conjugated to different amino groups on the antibody.
  • the monoclonal antibody is cancer antigen specific, non-immunogenic, low toxicity, and internalized by cancer cells;
  • the cytotoxin is highly potent and is suitable for linker attachment; while the linker may be specific for cysteine (S) or lysine (N) binding, is stable in circulation, may be protease cleavable and/or pH sensitive, and is suitable for attachment to the cytotoxin.
  • Anticancer ADCs approved for therapeutic use in the USA include
  • brentuximab vedotin (ADCETRIS ® ), a chimeric anti-CD30 antibody conjugated to monomethylauristatin E used in anaplastic large cell lymphoma and Hodgkin lymphoma; and gemtuzumab ozogamicin (MYLOTARG ® ), a humanized anti-CD33 antibody conjugated to calicheamicin ⁇ used in acute myelogeneous leukemia - though this was withdrawn in 2010 for lack of efficacy.
  • ADCETRIS ® a chimeric anti-CD30 antibody conjugated to monomethylauristatin E used in anaplastic large cell lymphoma and Hodgkin lymphoma
  • gemtuzumab ozogamicin (MYLOTARG ® ), a humanized anti-CD33 antibody conjugated to calicheamicin ⁇ used in acute myelogeneous leukemia - though this was withdrawn in 2010 for lack of efficacy.
  • trastuzumab has been conjugated to the maytansinoid drug mertansine to form the ADC trastuzumab emtansine, also called trastuzumab-DM1 or trastuzumab-MC-DM1, abbreviated T-DM1 (LoRusso et al., "Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor 2-Positive Cancer", Clin. Cancer Res.
  • trastuzumab emtansine a novel antibody-drug conjugate for HER2-positive breast cancer
  • the mertansine is conjugated to the trastuzumab through a maleimidocaproyl (MC) linker which bonds at the maleimide to the 4-thiovaleric acid terminus of the mertansine side chain and forms an amide bond between the carboxyl group of the linker and a lysine basic amine of the trastuzumab.
  • MC maleimidocaproyl
  • Trastuzumab has 88 lysines (and 32 cysteines).
  • heterogeneous containing dozens of different molecules containing from 0 to 8 mertansine units per trastuzumab, with an average mertansine/trastuzumab ratio of 3.4.
  • Antibody cysteines can also be used for conjugation to cytotoxins through linkers that contain maleimides or other thiol specific functional groups.
  • a typical antibody contains 4, or sometimes 5, interchain disulfide bonds (2 between the heavy chains and 2 between heavy and light chains) that covalently bond the heavy and light chains together and contribute to the stability of the antibodies in vivo.
  • interchain disulfides can be selectively reduced with dithiothreitol, tris(2-carboxyethyl)phosphine, or other mild reducing agents to afford 8 reactive sulfhydryl groups for conjugation.
  • Cysteine linked ADCs are less heterogeneous than lysine linked ADCs because there are fewer potential conjugation sites; however, they also tend to be less stable due to partial loss of the interchain disulfide bonds during conjugation, since current cysteine linkers bond to only one sulfur atom.
  • the optimal number of cytotoxins per antibody for cysteine linked ADCs is also 2 to 4.
  • ADCETRIS is a heterogeneous mixture that contains 0 to 8 monomethylauristatin E residues per antibody conjugated through cysteines.
  • Schumacher et al. "In Situ Maleimide Bridging of Disulfides and a New Approach to Protein PEGylation", Bioconjugate Chem. 2011, 22, 132-136, disclose the synthesis of 3,4-disubstituted maleimides such as 3,4-bis(2- hydroxyethylsulfanyl)pyrrole-2,5-dione [referred to by Schumacher et al. as
  • linker of the following formula (I)
  • each X and X' is independently O, S, NH or NR 1 wherein R 1 is C 1-3 alkyl;
  • each Y and Y' is independently hydrogen or an electrophilic leaving group that
  • W is -NH-, -N(R 1 )-, -CH 2 -, -CH 2 -NH-, -CH 2 -N(R 1 )-, -CH 2 CH 2 -, -CH(R 2 )-, or
  • R 1 and R 2 are independently C 1-3 alkyl
  • Z is -CO 2 H, -NH 2 , -OH, -NH-R 3a , or -CO 2 R 3b ; wherein R 3a is an amino protecting group, and R 3b is a carboxyl protecting group;
  • R is any chemical group; or R is absent;
  • each L 1 , L 2 and L 3 is independently a linker selected from the group consisting of -O-, -C(O)-, -S-, -S(O)-, -S(O) 2 -, -NH-, -NCH 3 -, -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) p ,
  • a, b and c are each independently an integer of 0, 1, 2 or 3, provided that at least one of a, b or c is 1;
  • each q is independently an integer or 1 to 12;
  • each AA is independently an amino acid
  • each r is 1 to 12;
  • the bond represents a single or a double bond.
  • the bond represents a single bond.
  • each Y and Y' is
  • each Y and Y' is independently selected from the group consisting of chloro, bromo, fluoro, and iodo.
  • each Y and Y' is independently selected from an optionally substituted thiophenyl, an optionally substituted thionaphthyl, an optionally substitued thiopyridyl, an optionally substituted isoquinolinyl, and an optionally substituted phenylsulfonate.
  • each Y and Y' is
  • RA is selected from the group consisting of hydroxyl, amino, nitro, cyano, chloro, bromo, fluoro, iodo, oxo, carboxyl, C 1-6 alkoxycarbonyl, C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy.
  • each Y and Y' is
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -(CH 2 ) q -, -NH(CH 2 ) 2 NH-,
  • each AA is an amino acid selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val.
  • each AA is an amino acid selected from the group consisting of Gly, Arg, Val, Ala, Cys, Gin, Leu, lie, Leu, Lys and Ser or their N-methylated analogues.
  • R 3a is selected from the group consisting of 9-fluorenylmethyloxycarbamate (FMOC), tert-butyloxycarbonyl (BOC), benzyl carbamate (Cbz), acetamide, trifluroacetamide, phthalimide,
  • benzylamine triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide (p- TOS).
  • R 3b is selected from the group consisting of a methyl ester, a tert-butyl ester, a benzyl ester, an S-tert-butyl ester, and 2-alkyl-1,3-oxazoline.
  • R is selected from the group consisting of W, (L 1 ) a , (L 2 ) b , (L 3 ) c , Z, W-(L 1 ) a -(L 2 ) b -(l_ 3 ) c , (L 1 ) a -(L 2 ) b -(L 3 ) c -Z, and W- (L 1 )a-(L 2 ) b -(L 3 ) c -Z, as defined above.
  • R is a detectable probe.
  • k and k' are both 1.
  • linker-cytotoxin conjugate of the following formula (II):
  • each X and X' is independently O, S, NH or NR 1 wherein R 1 is C 1-3 alkyl;
  • each Y and Y' is independently hydrogen or an electrophilic leaving group that
  • W is -NH-, -N(R 1 )-, -CH 2 -, -CH 2 -NH-, -CH 2 -N(R 1 )-, -CH 2 CH 2 -, -CH(R 2 )-, or
  • R 1 and R 2 are independently C 1-3 alkyl
  • CTX is a cytotoxin
  • R is any chemical group; or R is absent;
  • each L 1 , L 2 and L 3 is independently a linker selected from the group consisting of -O-, -C(O)-, -S-, -S(O)-, -S(O) 2 -, -NH-, -NCH 3 -, -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) p ,
  • a, b and c are each independently an integer of 0, 1, 2 or 3, provided that at least one of a, b or c is 1;
  • each k and k' is independently an integer of 0 or 1 ;
  • each p is independently an integer of 1 to 14;
  • each q is independently an integer or 1 to 12;
  • n is an integer of 1 to 4.
  • the bond represents a single or a double bond.
  • the bond represents a single bond.
  • CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via an amide, an N-(C 1-6 alkyl)amide, a carbamate, an N-(C 1-6 alkyl)carbamate, an amine, an N-(C 1-6 alkyl)amine, an ether, a thioether, an urea, an N- (C 1-6 alkyl)urea, or an N,N-di(C 1-6 alkyl)urea bond.
  • CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via a bond selected from the group consisting of:
  • each R B is independently branched or unbranched C 1-6 alkyl.
  • CTX is selected from a from the group consisting of a tubulin stabilizer, a tubulin destabilizer, a DNA alkylator, a DNA minor groove binder, a DNA intercalator, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a gyrase inhibitor, a protein synthesis inhibitor, a proteosome inhibitor, and an anti-metabolite.
  • the CTX is selected from the group consisting of Actinomycin-D, Amonafide, an auristatin, benzophenone, benzothiazole, a calicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin, Colchicine, Combretastatin A4, Dolastatin, Doxorubicin, Elinafide,
  • Emtansine (DM1), Etoposide, KF-12347 (Leinamycin), a maytansinoid, Methotrexate, Mitoxantrone, Nocodazole, Proteosome Inhibitor 1 (PSI 1), Roridin A, T-2 Toxin
  • R is selected from the group consisting of W, (L 1 ) a , (L 2 ) b , (L 3 ) c , Z, W-(L 1 ) a -(L 2 ) b -(L 3 ) c , (L 1 ) a - (L 2 ) b -(L 3 ) C -Z, and W-(L 1 )a-(L 2 ) b -(L 3 ) c -Z, as defined above.
  • R is a detectable probe.
  • R is an antibody fragment.
  • A is an antibody or antibody fragment
  • cysteine residues are from an opened cysteine-cysteine disulfide
  • each X and X' is independently O, S, NH or NR 1 wherein R 1 is C 1-3 alkyl;
  • W is -NH-, -N(R 1 )-, -CH 2 -, -CH 2 -NH-, -CH 2 -N(R 1 )-, -CH 2 CH 2 -, -CH(R 2 )-, or
  • R 1 and R 2 are independently C 1-3 alkyl
  • CTX is a cytotoxin
  • R is any chemical group; or R is absent;
  • each L 1 , L 2 and L 3 is independently a linker selected from the group consisting of -O- -C(O)-, -S-, -S(O)-, -S(O) 2 -, -NH-, -NCH 3 -, -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) p , -(CH 2 CH 2 O) p CH 2 CH 2 -, -CH 2 CH 2 -(CH 2 CH 2 O) p -, -OCH(CH 2 O-) 2
  • a, b and c are each independently an integer of 0, 1, 2 or 3, provided that at least
  • one of a, b or c is 1;
  • each k and k' is independently an integer of 0 or 1 ;
  • each p is independently an integer of 1 to 14;
  • each q is independently an integer or 1 to 12;
  • each AA is independently an amino acid
  • each r is 1 to 12;
  • n is an integer of 1 to 4.
  • n is an integer of 1 to 4.
  • the bond represents a single or a double bond.
  • the bond represents a single bond.
  • A is an antibody that is specific to a cancer antigen.
  • A is selected from the group consisting of alemtuzumab, anitumumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, glembatumumab, inotuzumab, ipilimumab, lovortumumab, milatuzumab, ofatumumab, rituximab, tositumomab, and trastuzumab.
  • CTX is selected from a from the group consisting of a tubulin stabilizer, a tubulin destabilizer, a DNA alkylator, a DNA minor groove binder, a DNA intercalator, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a gyrase inhibitor, a protein synthesis inhibitor, a proteosome inhibitor, and an anti-metabolite.
  • the CTX is selected from the group consisting of Actinomycin D, Amonafide, an auristatin, benzophenone, benzothiazole, a calicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin, Colchicine, Combretastatin A4, Dolastatin, Doxorubicin, Elinafide,
  • Emtansine (DM1), Etoposide, KF-12347 (Leinamycin), a maytansinoid, Methotrexate, Mitoxantrone, Nocodazole, Proteosome Inhibitor 1 (PSI 1), Roridin A, T-2 Toxin
  • the CTX is an auristatin, a calicheamicin, a maytansinoid, or a tubulysin.
  • the CTX is monomethylauristatin E, monomethylauristatin F, calicheamicin ⁇ , mertansine, tubulysin T3, or tubulysin T4.
  • R is selected from the group consisting of W, (L 1 ) a , (L 2 ) b , (L 3 ) c , Z, W-(L 1 ) a -(L 2 ) b -(l_ 3 ) c , (L 1 ) a - (L 2 ) b -(L 3 ) c -Z, and W-(L 1 ) a -(L 2 ) b -(L 3 ) c -Z, as defined above.
  • R is a detectable probe.
  • k and k' are both 1.
  • a pharmaceutical composition comprising the antibody-drug conjugate of formula (III) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluents, carrier or excipient.
  • a method of treating a cancer by administering to a human suffering therefrom an effective amount of the antibody-drug conjugate of formula (III) or a pharmaceutical composition comprising such antibody-drug conjugate.
  • Figure 1 Human IgG Sub-types
  • Figure 2 Forms of Antibodies and Antibody Fragments
  • an "antibody,” also known as an immunoglobulin, is a large Y-shaped protein that binds to an antigen. Antibodies are used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the antigen, because each tip of the "Y" of the antibody contains a site that is specific to a site on an antigen, allowing these two structures to bind with precision.
  • An antibody may consist of four polypeptide chains, two heavy chains and two light chains connected by interchain cysteine disulfide bonds (see, e.g., Figure 1).
  • a “monoclonal antibody” is a monospecific antibody where all the antibody molecules are identical because they are made by identical immune cells that are all clones of a unique parent cell. Initially, monoclonal antibodies are typically prepared by fusing myeloma cells with the spleen cells from a mouse (or B-cells from a rabbit) that has been immunized with the desired antigen, then purifying the resulting hybridomas by such techniques as affinity purification.
  • Recombinant monoclonal antibodies are prepared in viruses or yeast cells rather than in mice, through technologies referred to as repertoire cloning or phage display/yeast display, the cloning of immunoglobulin gene segments to create libraries of antibodies with slightly different amino acid sequences from which antibodies with desired specificities may be obtained.
  • the resulting antibodies may be prepared on a large scale by fermentation.
  • "Chimeric” or “humanized” antibodies are antibodies containing a combination of the original (usually mouse) and human DNA sequences used in the recombinant process, such as those in which mouse DNA encoding the binding portion of a monoclonal antibody is merged with human antibody- producing DNA to yield a partially-mouse, partially-human monoclonal antibody.
  • Antibodies and "immunoglobulins" (Igs) are glycoproteins having similar structural characteristics. While antibodies exhibit binding specificity to a specific antigen, immunoglobulins include both antibodies and other antibody-like molecules which generally lack antigen specificity. Polypeptides of antibody-like molecules are produced at low levels by the lymph system and at increased levels by myelomas.
  • antibody and “immunoglobulin” are used interchangeably in the broadest sense and include monoclonal antibodies ⁇ e.g., full length or intact monoclonal antibodies), polyclonal antibodies, monovalent antibodies, multivalent antibodies, multispecific antibodies ⁇ e.g., bispecific antibodies so long as they exhibit the desired biological activity).
  • Forms of antibodies and antibody fragments are shown schematically in Figure 2. These antibodies may also include certain antibody fragments.
  • An antibody can be chimeric, human, humanized and/or affinity matured. Exemplary antibodies are shown in Figure 3.
  • Antibodies of particular interest are those that are specific to cancer antigens, are non-immunogenic, have low toxicity, and are readily internalized by cancer cells; and suitable antibodies include alemtuzumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, inotuzumab, glembatumunnab, lovortuzumab and trastuzumab.
  • Additional antibodies include adecatumumab, afutuzumab, bavituximab, belimumab, bivatuzumab, cantuzumab, citatuzumab, cixutumumab, conatumumab, dacetuzumab, elotuzumab, etaracizumab, farletuzumab, figitumumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lucatumumab, mapatumunnab, matuzumab, milatuzumab, necitumumab, nimotuzumab, olaratumab, oportuzumab, pertuzumab, pritumumab, ranibizumab, robatumumab, sibrotuzumab, siltuximab, tacatuzumab
  • full length antibody “intact antibody” and “whole antibody” are used herein interchangeably to refer to an antibody in its substantially intact form, and are not antibody fragments as defined below. The terms particularly refer to an antibody with heavy chains that contain the Fc region.
  • Antibody fragments comprise only a portion of an intact antibody, wherein the portion retains at least one, two, three and as many as most or all of the functions normally associated with that portion when present in an intact antibody.
  • an antibody fragment comprises an antigen binding site of the intact antibody and thus retains the ability to bind antigen.
  • an antibody fragment such as an antibody fragment that comprises the Fc region, retains at least one of the biological functions normally associated with the Fc region when present in an intact antibody. Such functions may include FcRn binding, antibody half life modulation, ADCC function and complement binding.
  • an antibody fragment is a monovalent antibody that has an in vivo half life substantially similar to an intact antibody.
  • such an antibody fragment may comprise on antigen binding arm linked to an Fc sequence capable of conferring in vivo stability to the fragment.
  • the term "monoclonal antibody,” as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible mutations, e.g., naturally occurring mutations, that may be present in minor amounts.
  • the modifier term "monoclonal” indicates the character of the antibody as not being a mixture of discrete antibodies.
  • such a monoclonal antibody may include an antibody comprising a polypeptide sequence that binds a target, wherein the target-binding polypeptide sequence was obtained by a process that includes the selection of a single target binding polypeptide sequence from a plurality of polypeptide sequences.
  • the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, or recombinant DNA clones.
  • a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, or recombinant DNA clones.
  • monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins.
  • the monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding
  • Humanized forms of non-human ⁇ e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from a hypervanable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or nonhuman primate having the desired specificity, affinity, and/or capacity.
  • FR residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all the FRs are those of a human immunoglobulin sequence.
  • the humanized antibody may comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. See Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1 :105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994).
  • Fc receptor or “FcR” is a receptor that binds to the Fc region of an antibody.
  • an FcR is a native human FcR.
  • an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII and Fc ⁇ RIII subclasses. (See Daeron, Annu. Rev. Immunol. 15:203-234 (1997)).
  • alkyl means a straight, branched chain, or cyclic (in this case, it would also be known as "cycloalkyl") hydrocarbon containing from 1-10 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, and n- decyl.
  • such alkyl groups can optionally be substituted with 1 to 5 substituents selected from the group consisting of halo, cyano, nitro, CF 3 -, CF 3 O-, CH 3 O-, -CO2H, -C(O)CH 3 , -NH 2 , -OH, -SH, -NHCH 3 , -N(CH 3 ) 2 , -SMe, and the like.
  • C 1-6 alkyl means a straight, branched chain, or cyclic (in this case, it would also be known as “cycloalkyl”) hydrocarbon containing from 1-6 carbon atoms.
  • C 1- 3alkyl means a straight or branched chain hydrocarbon containing from 1-3 carbon atoms.
  • alkenyl means a straight, branched chain, or cyclic (in which case, it would also be known as a “cycloalkenyl”) hydrocarbon containing from 2-10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • an alkenyl group is a monoradical or a diradical (i.e., an alkenylene group).
  • alkenyl groups are optionally substituted.
  • alkenyl examples include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4- pentenyl, 5-hexenyl, 2-heptenyl, and 2-methyl-1-heptenyl.
  • such alkenyl groups can optionally be substituted with 1 to 5 substituents selected from the group consisting of halo, cyano, nitro, CF 3 -, CF 3 O-, CH 3 O-, -CO 2 H, -C(O)CH 3 , -NH 2 , -OH, -SH, -NHCH 3 , -N(CH 3 ) 2 , -SMe, and the like.
  • alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • C 2 -6 alkenyl means a straight, branched chain, or cyclic (in this case, it would also be known as “cycloalkyl”) hydrocarbon containing from 2-6 carbon atoms and at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • cycloalkyl means a monocyclic or polycyclic radical that contains only carbon and hydrogen, and includes those that are saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • amino refers to the radical -NH 2 .
  • hydroxyl or "hydroxy,” as used herein, refers to the radical -OH.
  • phenyl refers to a C 6 H 5 group as known in the art.
  • Phenylene refeers to a divalent phenyl group, wherein the phenyl group is substituted at two positions on the phenyl ring that may be ortho (o-C 6 H ) or para (p-C 6 H 4 ).
  • thiol refers to the radical -SH.
  • substituted thiol refers to a radical such as -SR wherein R is any optionally substituted chemical group described herein.
  • substituted thiol refers to a radical -SR where R is an alkyl, cycloalkyl, aryl or heteroaryl group as defined herein that may be optionally substituted as defined herein.
  • Representative examples of substituted thiol include, but are not limited to, thioph thionaphthyl, thiopyridyl, thioisoquinolinyl, as depicted below:
  • sulfonate refers to the radical -OS(O 2 )H.
  • substituted sulfonate refers to a radical such as -OS(O 2 )R wherein R is an alkyl, cycloalkyi, aryl or heteroaryl group as defined herein that may be optionally substituted as defined herein. In certain embodiments, R is selected from lower alkyl, alkyl, aryl and heteroaryl.
  • Representative examples of substituted sulfonate include, but are not limited to, tosylate, mesylate and triflate, as depicted below:
  • aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring ⁇ e.g., phenyl) or multiple condensed rings ⁇ e.g., naphthyl or anthryl).
  • Preferred aryls include phenyl, biphenyl, naphthyl and the like.
  • such aryl groups can optionally be substituted with 1 or more substituents, for example, 1 to 5 substituents, such as, hydroxyl, amino, nitro, cyano, chloro, bromo, fluoro, iodo, oxo, carboxyl, C 1-6 alkoxycarbonyl, C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy, and the like.
  • substituents for example, 1 to 5 substituents, such as, hydroxyl, amino, nitro, cyano, chloro, bromo, fluoro, iodo, oxo, carboxyl, C 1-6 alkoxycarbonyl, C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy, and the like.
  • such aryl groups can optionally be substituted with 1 to 5 substituents selected from the group consisting of halo, cyano, nitro, CF 3 -, CF 3 O-, CH 3 O-, -CO2H, -C(O)CH 3 , -NH 2 , -OH, -SH, -NHCH 3 , -N(CH 3 ) 2 , -SMe and C 1-3 alkyl.
  • heteroaryl refers to an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. Preferably, the heterocyclic ring system is monocyclic or bicyclic.
  • heteroaryl groups can optionally be substituted with 1 or more substituents, for example, 1 to 5 substituents, such as, hydroxyl, amino, nitro, cyano, chloro, bromo, fluoro, iodo, oxo, carboxyl, C 1-6 alkoxycarbonyl, C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy, and the like.
  • substituents for example, 1 to 5 substituents, such as, hydroxyl, amino, nitro, cyano, chloro, bromo, fluoro, iodo, oxo, carboxyl, C 1-6 alkoxycarbonyl, C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy, and the like.
  • heteroaryl groups can optionally be substituted with 1 to 5 substituents selected from the group consisting of halo, cyano, nitro, CF 3 -, CF 3 O-, CH 3 O-, -CO2H, -C(O)CH 3 , -NH 2 , -OH, -SH, -NHCH 3 , -N(CH 3 ) 2 , -SMe and C 1-3 alkyl.
  • substituents selected from the group consisting of halo, cyano, nitro, CF 3 -, CF 3 O-, CH 3 O-, -CO2H, -C(O)CH 3 , -NH 2 , -OH, -SH, -NHCH 3 , -N(CH 3 ) 2 , -SMe and C 1-3 alkyl.
  • hetroaryl include, but are not limited to:
  • chemical group refers to two or more atoms bound together as a single unit and forming part of a molecule.
  • protecting group refers to a chemical group that is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity. Examples of protecting groups are disclosed, for example, in Greene, T. W. and Wuts, P. G. M., 1991, Protective Groups In Organic Synthesis, 3rd ed.; John Wiley & Sons: New York, and similar documents.
  • amino protecting group refers to a protecting group that serves to protect an amino functional group.
  • the term includes, without limitation, 9-fluorenylmethyloxycarbamate (FMOC), tert-butyloxycarbonyl (BOC), benzyl carbamate (Cbz), acetamide, trifluroacetamide, phthalimide, benzylamine, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide (p-TOS), and the like.
  • carboxyl protecting group refers to a protecting group that serves to protect a carboxylic acid functional group.
  • the term includes, without limitation, a methyl ester, a tert-butyl ester, a benzyl ester, an S-tert-butyl ester, 2-alkyl-1,3-oxazoline, and the like.
  • amino acid or AA or amino acid residue includes all 20 naturally occurring amino acids, commonly designated by three letter symbols ⁇ e.g., alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gin), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (lie), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val)).
  • the amino acid residue of the present application also includes citrulline (Cit), 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, homocysteine, homoserine, ornithine and methionine sulfone.
  • the amino acid residue of the present application also includes the corresponding N-methyl amino acids, such as -N(CH 3 )CH 2 C(O)O-, -NHC(O)CH 2 CH 2 CH(NHCH 3 )C(O)O-, etc.
  • amino acids, dipeptides, tripeptides, oligomers and polypeptides designated as -(AA )r - of the present application may include the corresponding non-N-alkylated amino acids and peptides (such as non-N-methylated amino acids in the peptides), as well as a mixture of the non- N-alkylated amino acids and the N-alkylated amino acids of the peptides.
  • a "cytotoxin” is a molecule that, when released within a cancer cell, is toxic to that cell.
  • a "linker” (noted as L or L 1 , L 2 and L 3 ) is a molecule with two reactive termini, one for conjugation to an antibody or to another linker and the other for conjugation to a cytotoxin.
  • the antibody conjugation reactive terminus of the linker is typically a site that is capable of conjugation to the antibody through a cysteine thiol or lysine amine group on the antibody, and so is typically a thiol-reactive group such as a double bond (as in maleimide) or a leaving group such as a chloro, bromo or iodo or an R-sulfanyl group or sulfonyl group, or an amine-reactive group such as a carboxyl group or as defined herein; while the antibody conjugation reactive terminus of the linker is typically a site that is capable of conjugation to the cytotoxin through formation of an amide bond with a basic amine or carboxyl group on the cytotoxin, and so is typically a carboxyl or basic amine group.
  • a thiol-reactive group such as a double bond (as in maleimide) or a leaving group such as a chloro, bromo or io
  • linker when the term "linker" is used in describing the linker in conjugated form, one or both of the reactive termini will be absent (such as the leaving group of the thiol-reactive group) or incomplete (such as the being only the carbonyl of the carboxylic acid) because of the formation of the bonds between the linker and/or the cytotoxin.
  • leaving group refers to any group that leaves in the course of a chemical reaction involving the group as described herein and includes but is not limited to halogen, sulfonates (brosylate, mesylate, tosylate triflate etc ...), p-nitrobenzoate and phosphonate groups, for example.
  • electrophilic leaving group refers to a leaving group that accepts an electron pair to make a covalent bond.
  • electrophiles are susceptible to attack by complementary nucleophiles, including the reduced thiols from the disulfide bond of an antibody.
  • electrophilic leaving group that reacts selectively with thiols refers to electrophilic leaving group that reacts selectively with thiols, over other nucleophiles.
  • an electrophilic leaving group that reacts selectively with thiols reacts selectively with the reduced thiols from the disulfide bond of an antibody.
  • detectable probe refers to a composition that provides a detectable signal.
  • the term includes, without limitation, any fluorophore, chromophore, radiolabel, enzyme, antibody or antibody fragment, and the like, that provide a detectable signal via its activity.
  • ADC antibody-drug conjugate
  • the antibody is typically a monoclonal antibody specific to a therapeutic target such as a cancer antigen.
  • a "cytotoxic agent” or “cytotoxin” is a molecule that has a cytotoxic effect on cells ⁇ e.g., when released within a cancer cell, is toxic to that cell).
  • Tubulysin includes both the natural products described as tubulysins, such as by Sasse et al. and other authors mentioned in the Description of the related art, and also the tubulysin analogs described in US Patent Application Publication No. US 2011/0021568 A1.
  • Tubulysins disclosed in the present application are noted herein and may include the tubulysins of the formulae T3 and T4, and other tubulysins where the terminal N-methylpiperidine has been replaced by an unsubstituted piperid illustrated below for T3 and T4:
  • MMAF generally refers to (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-
  • MMAF may refer to ((2R,3R)-3-((S)-1-((3R,4S,5R)-4-((S)-
  • cell proliferative disorder and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation.
  • the cell-pr-liferative disorder is cancer.
  • Tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • a “therapeutically effective amount” means that amount of an ADC or composition disclosed herein which, when administered to a human suffering from a cancer, is sufficient to effect treatment for the cancer.
  • Treating" or “treatment” of the cancer includes one or more of:
  • the term "pharmaceutically acceptable salt” refers to those salts of the ADCs formed by the process of the present application which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically
  • salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the ADC compounds, or separately by reacting the free base function or group of a compound with a suitable organic acid.
  • suitable organic acid examples include, but are not limited to, nontoxic acid addition salts, or salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc., or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • salts include, but are not limited to, adipate, alginate, ascorbate, benzenesulfonate, benzoate, bisulfate, citrate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, 2-hydroxy-ethanesulfonate, lactate, laurate, malate, maleate, malonate, methanesulfonate, oleate, oxalate, palmitate, phosphate, propionate, stearate, succinate, sulfate, tartrate, p-toluenesulfonate, valerate salts, and the like.
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, or magnesium salts, and the like.
  • Further pharmaceutically acceptable salts include, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl groups having from 1 to 6 carbon atoms (e.g., C 1-6 alkyl), sulfonate and aryl sulfonate.
  • Cancers of interest for treatment include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g.
  • lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, oral cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer including, for example, HER2-positive breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CML), multiple myeloma and B-cell lymphoma, brain cancer, head and neck cancers and associated metastases.
  • lung cancer including small-cell lung cancer, non-small cell lung
  • ADC antibody-drug conjugate
  • BOC tert-butyloxycarbonyl
  • BRA tert-butyloxycarbonyl
  • DIAD diisopropyl azodicarboxylate
  • DIPC diisopropyl azodicarboxylate
  • DIPEA diisopropylethylamine
  • DMA dimethyacetamide
  • DMF N,N-dimethylformamide
  • DPBS Dulbecco's phosphate-buffered saline
  • DTNB 5,5'-dithiobis-(2-nitrobenzoic acid)
  • DTPA diethylenetriaminepentaacetic acid
  • DTT dithiothreitol
  • EDC ethyl 3-(3-dimethylaminopropyl)carbodiimide
  • EEDQ EEDQ:
  • HATU 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
  • N-hydroxybenzotriazole HPLC: High Performance Liquid Chromatography
  • NHS N-hydroxysuccinimide
  • NMM N-methylmorpholine
  • MC maleimido caproyl
  • MMAE monomethylauristatin E
  • MMAF monomethylauristatin F, monomethylauristatin phenylalanine
  • MC nnaleinnidocaproyi, 6-(2,5-dioxopyrrolyl)hexanoyl
  • PAB para amino benzyl
  • PBD pyrrolobenzodiazepine
  • PBS phosphate-buffered saline
  • PEG phosphate-buffered saline
  • PEG PEG:
  • VA(PAB) Valine-Alanine-para amino benzyl.
  • ATZ alemtuzumab
  • ATM anitumumab
  • BCZ bevacizumab
  • BTX brentuximab
  • CTX cetuximab
  • GTZ gemtuzumab
  • GBT glembatumumab
  • ITZ inotuzumab
  • ILM ipilimumab
  • LVT lovortumumab
  • MTZ milatuzumab
  • OTM ofatumumab
  • RTX rituximab
  • TTM tositumomab
  • TTZ trastuzumab
  • linkers disclosed herein are "opened ring" structures, such that the linker is capable of being chemically modified at two positions of the structure, the Z position, and the R position (see arrowed positions below):
  • linkers disclosed herein which have "opened ring” structures, display improved in vivo stability with regard to the antibody-linker interface.
  • the "opened ring" structure of the linkers disclosed herein also allow greater flexibility in making ADCs capable of carrying two drug payloads or one drug payload and a detectable probe, as explained below.
  • two cytotoxin (CTX) molecules may be conjugated to the linker.
  • Such linker may be used to make an ADC that is capable of carrying two drug payloads.
  • R is "capped off' with an unreactive side chain
  • R is W, (L 1 ) a , (L 2 ) b , (L 3 ) c , or W-(L 1 )a-(L 2 )b-(L 3 ) c
  • only one CTX may be conjugated to the linker.
  • Such linker may be used to make an ADC that is capable of carrying one drug payload.
  • R is a detectable probe ⁇ e.g., a fluorophore, chromophore, radiolabel, enzyme, antibody or antibody fragment that provides a detectable signal via its activity
  • a linker may be used to make an ADC capable of carrying one drug payload and a detectable probe.
  • R is a radiolabel
  • such a linker may be used to make an ADC that is capable of carrying one drug payload (CTX) and one radiolabel.
  • CTX drug payload
  • the resultant radiolabeled ADC can be useful for imaging and/or therapy.
  • ADCs of the prior art that coordinate to cysteine thiols of the antibody have employed monofunctional linkers, of which the MC linker is an example. Reduction and opening of the cysteine-cysteine disulfide bonds to give free thiols for conjugation decreases the stability of the antibody, and the formation of the ADC by reaction of the reduced thiols does not re-form the interchain disulfide bond, as illustrated for an exemplary antibody depicted with four interchain disulfide bonds in the following Scheme A:
  • ADCs may comprise all possible positional isomers of drug conjugate to cysteine thiol, and may comprise all possible drug antibody ratios (1, 2, 3, 4, .., and 8).
  • the linkers disclosed herein contain two reactive functional groups (Y and Y' in the scheme below) that selectively target the two sulfur atoms of an opened cysteine-cysteine disulfide bond ⁇ e.g., one or more opened interchain cysteine-cysteine disulfide bonds).
  • Reaction of the bifunctional linker with the two cysteines of an opened cysteine-cysteine disulfide bond gives a "stapled” or "snapped” antibody conjugate with one linker per disulfide ⁇ e.g., one or more interchain disulfides) connected through two thioether bonds, as shown in the following exemplary Scheme B:
  • linker-cytotoxin conjugate is represented by a cartoon, where the linker between W and CTX is the squiggly line, k and k' are both 0, m is 1, and R is the black dot.
  • a homogenous ADC for example, with an drug-to-antibody ratio of four (4) is produced.
  • Scheme B depicts a homogenous ADC, where, for example, the four (4) interchain disulfide bonds of the antibody (2 H-H disulfide bonds, and 2 H-L disulfide bonds) are conjugated.
  • the reaction re-forms a covalently bonded structure between the 2 cysteine sulfur atoms and therefore does not compromise the overall stability of the antibody.
  • the method also enables conjugation of an optimal 4 drugs for an antibody to afford a homogeneous ADC in which the reactive cysteines are used.
  • the overall result is replacement of a relatively labile disulfide with a stable "staple” or "snap" between the cysteines.
  • the monosubstituted linkers (where one of Y and Y' is hydrogen) are also effectively bifunctional in
  • conjugation with the antibody because the double bond is capable of conjugation to one of the cysteine sulfur atoms and the Y group with the other.
  • Linkers may be prepared by methods well known to a person of ordinary skill in the art, following procedures described in such references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, N.Y., 1991 ; March J.: Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.
  • linkers disclosed herein may be cleavable under normal physiological and/or intracellular conditions, or may remain stable ⁇ e.g., uncleaved or non-cleavable) under those same conditions.
  • cleavable linkers may remain stable during systemic circulation but may be cleaved under certain intracellular conditions, such as in an acidic
  • the linker may be cleaved by the acidic environment and/or the enzymes in the lysosome, releasing the cytotoxin from the antibody.
  • cleavable linkers are linkers which contain dipeptide moieties, where the peptide bond connecting the two peptides has the potential to be selectively cleaved by lysosomal proteases (e.g., cathepsin-B).
  • Valine-citruline (Val-Cit) is a dipeptide moiety commonly used in cleavable linkers.
  • Noncleavable linkers may remain stable, both during systemic circulation and under certain intracellular conditions, such as in an acidic environment.
  • stable linkers are linkers which do not contain dipeptide moieties, for example, alkyl and/or PEG linkers.
  • stable linkers which may be synthesized by the methods disclosed herein are provided below:
  • Linker-cytotoxin conjugates may be prepared by methods analogous to those of Doronina et al., Bioconjugate Chem. 2006, 17, 114-124, and similar documents.
  • the linker, 1 equivalent, and HATU, 1 equivalent, are dissolved in anhydrous DMF, followed by the addition of DIPEA, 2 equivalents.
  • the resulting solution is added to the cytotoxin, 0.5 equivalents, dissolved in DMF, and the reaction stirred at ambient temperature for 3 hr.
  • the linker-cytotoxin conjugate is purified by reverse phase HPLC on a C-18 column.
  • linker-cytotoxin conjugates may be synthesized using any possible combination of linker and cytotoxin disclosed herein.
  • linker-cytotoxin conjugates (stable or cleavable linkers), where CTX may be any cytotoxin disclosed herein, and which may be synthesized by the methods disclosed herein, are provided below:
  • CTX e.g., tubulysins or modified tubulysins disclosed herein
  • the amine or carboxyl group may be part of the CTX molecule itself, as illustrated below for the following molecule fragment:
  • Antibodies typically monoclonal antibodies are raised against a specific cancer target (antigen), and purified and characterized.
  • Therapeutic ADCs containing that antibody are prepared by standard methods for cysteine conjugation, such as by methods analogous to those of Hamblett et al., "Effects of Drug Loading on the
  • Antibody-drug conjugates with four drugs per antibody are prepared by partial reduction of the antibody with an excess of a reducing reagent such as DTT or TCEP at 37 °C for 30 min, then the buffer exchanged by elution through SEPHADEX ® G-25 resin with 1 mM DTPA in DPBS. The eluent is diluted with further DPBS, and the thiol concentration of the antibody may be measured using 5,5'- dithiobis(2-nitrobenzoic acid) [Ellman's reagent].
  • a reducing reagent such as DTT or TCEP
  • the resulting ADC mixture may be purified on SEPHADEX G-25 equilibrated in PBS to remove unreacted Iinker-cytotoxin conjugate, desalted if desired, and purified by size- exclusion chromatography.
  • the resulting ADC may then be then sterile filtered, for example, through a 0.2 ⁇ filter, and lyophilized if desired for storage.
  • an ADC disclosed herein includes a homogenous ADC with a drug-to-antibody ratio of 4 (e.g., for an lgG1).
  • Scheme B above depicts a "Y"-shaped structure denoting an antibody, for example, an lgG1, where all four (4) interchain disulfide bonds of the antibody (2 H-H disulfide bonds, and 2 H-L disulfide bonds) are conjugated with a drug-to-antibody ratio of 4.
  • linker of the following formula (I):
  • each X and X' is independently O, S, NH or NR 1 wherein R 1 is C 1-6 alkyl;
  • each Y and Y' is independently hydrogen or an electrophilic leaving group that
  • W is -NH-, -N(R 1 )-, -CH 2 -, -CH 2 -NH-, -CH 2 -N(R 1 )-, -CH 2 CH 2 -, -CH(R 2 )-, or
  • R 1 and R 2 are independently C 1-6 alkyl
  • Z is -CO 2 H, -NH 2 , -OH, -NH-R 3a , or -CO 2 R 3b ; wherein R 3a is an amino protecting group, and R 3b is a carboxyl protecting group; or Z is any chemical group; R is any chemical group; or R is absent;
  • each L 1 , L 2 and L 3 is independently a linker selected from the group consisting of -O-, -C(O)-, -S-, -S(O)-, -S(O) 2 -, -NH-, -NCHs-, -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) p ,
  • a, b and c are each independently an integer of 0, 1, 2 or 3, provided that at least one of a, b or c is 1;
  • each k and k' is independently an integer of 0 or 1 ;
  • each p is independently an integer of 1 to 14;
  • each q is independently an integer or 1 to 12;
  • each AA is independently an amino acid
  • each r is 1 to 12;
  • the bond represents a single or a double bond.
  • k and k' are both 1.
  • ⁇ is a linker of the following formula ( ⁇ ):
  • each X and X' is independently O, S, NH or NR 1 wherein R 1 is C 1-6 alkyl;
  • each Y and Y' is independently hydrogen or an electrophilic leaving group that reacts selectively with thiols, provided if one of Y and Y' is hydrogen, the other is the electrophilic leaving group;
  • W is -NH-, -N(R 1 )-, -CH 2 -, -CH 2 -NH-, -CH 2 -N(R 1 )-, -CH 2 CH 2 -, -CH(R 2 )-, or
  • R 1 and R 2 are independently C1-6 alkyl
  • Z is -CO 2 H, -NH 2 , -OH, -NH-R 3a , or -CO 2 R 3b ; wherein R 3a is an amino protecting group, and R 3b is a carboxyl protecting group;
  • R is any chemical group, provided that R is not OH;
  • each L 1 , L 2 and L 3 is independently a linker selected from the group consisting of -O-, -C(O)-, -S-, -S(O)-, -S(O) 2 -, -NH-, -NCHs-, -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) pj
  • a, b and c are each independently an integer of 0, 1, 2 or 3, provided that at least one of a, b or c is 1;
  • each p is independently an integer of 1 to 14;
  • each q is independently an integer or 1 to 12;
  • each AA is independently an amino acid
  • each r is 1 to 12;
  • the bond represents a single or a double bond.
  • the bond represents a single bond. In certain embodiments of the linker of formula (I) or ( ⁇ ), the bond represents a double bond.
  • X and X' are O.
  • W is -NH- or -N(R 1 )-, wherein R 1 is C 1-6 alkyl. In certain embodiments, W is -NH- or -N(R 1 )-, wherein R 1 is C 1-3 alkyl. In certain embodiments, W is -CH 2 NH- or -CH 2 N(R 1 )-, wherein R 1 is C 1-6 alkyl. In certain embodiments, W is -CH 2 NH- or -CH 2 N(R 1 )-, wherein R 1 is C 1-3 alkyl.
  • W is -CH 2 -, -CH 2 CH 2 -, -CH(R 2 )-, or -CH 2 CH(R 2 ), wherein R 2 is C 1-6 alkyl. In certain embodiments, W is -CH 2 -,
  • X and X' are O, and W is -NH-.
  • each Y and Y' is independently hydrogen or an electrophilic leaving group that reacts selectively with thiol.
  • each Y and Y' is independently selected from the group consisting of a halo, a substituted thiol, and a substituted sulfonate.
  • each Y and Y' is independently selected from the group consisting of chloro, bromo, fluoro, and iodo.
  • each Y and Y' is independently selected from an optionally substituted thiophenyl, an optionally substituted thionaphthyl, an optionally substitued thiopyridyl, an optionally substituted isoquinolinyl, and an optionally substituted phenylsulfonate.
  • Y and Y' is a substituted thiol, the substituent is selected from the group consisting of C6-io aryl and ⁇ - ⁇ heteroaryl .
  • C 1-6 alkyl optionally substituted with halo or hydroxyl
  • phenyl optionally substituted with halo, hydroxyl, carboxyl, C 1-3 alkoxycarbonyl, or C h alkyl
  • naphthyl optionally substituted with halo, hydroxyl, carboxyl, C 1-3 alkoxycarbonyl, or C 1-3 alkyl
  • 2-pyridyl optionally substituted with halo, hydroxyl, carboxyl, C 1- 3alkoxycarbonyl or C 1-3 alkyl.
  • Y and Y' is a substituted sulfonate, the substituent is selected from the group consisting of C 1-6 alkyl, C2-iocycloalkyl, C6-ioaryl, and C6-ioheteroaryl.
  • each Y and Y' is independently selected from the group consisting of:
  • R A is selected from the group consisting of hydroxyl, amino, nitro, cyano, chloro, bromo, fluoro, iodo, oxo, carboxyl, C 1-6 alkoxycarbonyl, C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy.
  • R A is selected from the group consisting of halo, CF 3 -, CF 3 O-, CH 3 O-, -C(O)OH, -C(O)OC 1-3 alkyl, -C(O)CH 3 , -CN, -NH 2 , -OH, -NHCH 3 , -N(CH 3 ) 2 and C 1-3 alkyl.
  • each Y and Y' is independently selected from the group consisting of:
  • Z is -CO2H, -NH 2 , -OH, -NH-R 3a , or -CO 2 R 3b ; wherein R 3a is an amino protecting group, and R 3b is a carboxyl protecting group, as disclosed, for example, in Greene, T. W.; Wuts, P. G. M., 1991, Protective Groups In Organic Synthesis, 3rd ed.; John Wiley & Sons: New York, and similar documents. Those of ordinary skill in the art will be able to select appropriate amino or carboxyl protecting groups.
  • Z is -CO2H or -CO 2 R 3b , and R 3b is a carboxyl protecting group.
  • R 3a is selected from the group consisting of 9-fluorenylmethyloxycarbamate (FMOC), tert-butyloxycarbonyl (BOC), benzyl carbamate (Cbz), acetamide, trifluroacetamide, phthalimide,
  • benzylamine nitrobenzene, triphenylmethylamine, benzylideneamine, and p- toluenesulfonamide (p-TOS).
  • R 3b is selected from the group consisting of a methyl ester, a tert-butyl ester, a benzyl ester, an S-tert-butyl ester, and 2-alkyl-1,3-oxazoline.
  • Z is a detectable probe, a ligand, or an antibody.
  • Z is a fluorophore
  • chromophore chromophore, radiolabel, enzyme, ligand, antibody or antibody fragment.
  • R is selected from the group consisting of W, ( L1 )a , ( L2 )b , ( L3 )c , Z, W-( L1 )a -( L2 )b-( L3 )c, ( L1 )a -( L2 )b-( L3 )c-Z, and W-( L1 )a - ( L2 )b -( L3 )C -Z, as defined herein.
  • R is selected from the group consisting of W, ( L1 )a , ( L2 )b , ( L3 ) C , and W-( L1 )a -( L2 )b-( L3 ) C .
  • R is selected from the group consisting of Z, ( L1 ) a -( L2 )b-( L3 ) C - z > and W-( L1 )a -( L2 )b-( L3 ) C -Z.
  • R is a detectable probe.
  • R is a fluorophore, chromophore, radiolabel, enzyme, ligand, antibody or antibody fragment.
  • R is a ligand (e.g., a ligand specific for a receptor on a tumor cell, such as a prostate specific membrane antigen, or a virally infected cell, such as an HIV infected cell).
  • R is bonded to the rest of the linker molecule via an amide, an N-(C 1-6 alkyl)amide, a carbamate, an N-(C 1-6 alkyl)carbamate, an amine, an N-(C 1-6 alkyl)amine, an ether, a thioether, an urea, an N-(C 1-6 alkyl)urea, or an N,N-di(C 1-6 alkyl)urea bond.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO2-, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -C(O)NHCH 2 CH 2 -, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -C(O)CH 2 CH 2 -, -(CH 2 CH 2 O) p -, -(OCH 2 CH 2 ) p -, -(CH 2 CH 2 O) p CH 2 CH 2 -, -CH 2 CH 2 -(CH 2 CH 2 O) p -, -OCH 2 CH 2 ) p CH 2 CH 2 -, -CH 2 CH
  • a, b and c are each independently 0, 1 or 2; each p, q and r is independently 1, 2, 3 or 4.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) p , -(CH 2 CH 2 O) p CH 2 CH 2 -,
  • each p, q and r is independently 1, 2, 3 or 4.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -OCH(CH 2 O-) 2 and -C(O)NCH 3 -; a, b and c are each independently 0, 1 or 2; and each p and q is independently 1 or 2.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -NH(CH 2 ) 2 NH-, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -OCH(CH 2 O-) 2 and -C(O)NCH 3 -; and a, b and c are each
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -NHC(O)-, -C(O)NH-, -(CH 2 CH 2 O) p , -(CH 2 CH 2 O) p CH 2 CH 2 -, -CH 2 CH 2 -(CH 2 CH 2 O) p -, -OCH(CH 2 O-) 2 and -(AA)r-; a, b and c are each independently 0 or 1; and each p and r is independently 1, 2 or 3.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -NHC(O)-, -C(O)NH-,
  • one or more of the L 1 , L 2 and L 3 is -(AA) r -, wherein -(AA) r - is ValCit ⁇ e.g., the first amino acid is Valine, the second amino acid is Citrulline, and r is 1).
  • one or more of the L 1 , L 2 and L 3 is -(AA) r -, wherein -(AA)r is ValAla ⁇ e.g., the first amino acid is Valine, the second amino acid is
  • one or more of the L 1 , L 2 and L 3 is phenylenyl substituted by -C(O)OH and -NH 2 . In certain embodiments, one or more of the L 1 , L 2 and L 3 is phenylenyl substituted by -C(O)O- and -NH-. In certain embodiments, one or more of the L 1 , L 2 and L 3 is phenylenyl substituted by -OC(O)- and -NH-. In certain embodiments, one or more of the L 1 , L 2 and L 3 is phenylenyl substituted by -O- and -NH-. In certain embodiments, one or more of the L 1 , L 2 and L 3 is phenylenyl substituted by -O- and -NH-. In certain embodiments, one or more of the L 1 , L 2 and
  • L is a moiety of the following structure: .
  • one or more of the L 1 , L 2 and L 3 is a moiety of the following structure:
  • one or more of the L 1 , L 2 and L 3 is a moiety of the following structure: . In certain embodiments, one or more of the L 1 L 2 and L 3 is a moiet of the following structure:
  • one or more of the L 1 L 2 and L 3 is a moiet of the following structure:
  • one or more of the L 1 , L 2 and L 3 is a moiety of the following structure: . In certain embodiments, one or more of the L 1 ,
  • L 2 and L 3 is .
  • one or more of the L 1 , L 2 and L 3 is para aminobenzyl (PAB), which is optionally substituted with -C(O)O-, -OC(O)- or -O-.
  • PAB para aminobenzyl
  • each AA is an amino acid selected from the group consisting of Ala, Arg, Asn, Asp, Cit, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val.
  • (AA) r is a single amino acid selected from the group consisting of Cit, Gly, Arg, Val, Ala, Cys, Gin, Leu, lie, Leu, Lys and Ser or their N-methylated analogues.
  • (AA) r is selected from the group consisting of Ala-Val, Val-Ala, Gly-Gly, Gly-Arg, Gly-Val, Gly-Ala, Gly-Cys, Gly-GIn, Gly-lle, Leu, Lys-Leu, Gly- Lys, Val-Arg, Ala-Cit, Val-Cit, and Gly-Ser or their N-methylated analogues.
  • (AA) r is selected from the group consisting of Gly-Gly-Gly, Gly- Arg-Gly, Gly-Val-Gly, Gly-Ala-Gly, Gly-Cys-Gly, Gly-Gln-Gly, Gly-lle-Gly, Lys-Leu-Gly, Gly-Lys-Gly and Gly-Ser-Gly or their N-methylated analogues.
  • (AA) r is selected from the group consisting of Ala-Ala, Ala-Gly, Ala-Arg, Ala- Val, Ala-Ala, Ala-Cys, Ala-Gin, Ala-lie, Ala-Leu, Ala-Lys, Ala-Cit, and Ala-Ser or their N- methylated analogues.
  • (AA) r is selected from the group consisting of Ala-Ala-Ala, Ala-Gly-ALa, Ala-Arg-Ala, Ala-Val-Ala, Ala-Ala-Ala, Ala- Cys-Ala, Ala-Gln-Ala, Ala-lle-Ala, Ala-Leu-Ala, Ala-Lys-Ala and Ala-Ser-Ala or their N- methylated analogues.
  • L 1 is -(CH 2 ) q -, L 2 is absent, L 3 is absent, and Z is -CO 2 H.
  • L 1 is -(CH 2 ) q -
  • L 2 is - (OCH 2 CH 2 ) P -
  • L 3 is absent
  • Z is -CO 2 H.
  • L 1 is -(CH 2 CH 2 O) p -
  • L 2 is -(CH 2 ) q -
  • L 3 is absent
  • Z is -CO 2 H.
  • each L 1 is
  • L 2 is absent, L 3 is absent, and Z is -CO 2 H.
  • each L 1 is
  • L 2 is Val-Cit
  • L 3 is PAB
  • Z is -CO 2 H.
  • each L 1 is
  • L 2 is Val-Cit
  • L 3 is PAB
  • Z is -CO 2 H.
  • each L 1 is
  • L 2 is Val-Ala
  • L 3 is PAB
  • Z is -CO 2 H.
  • -(L 1 ) a -(L 2 ) b -(L 3 ) c - is selected from the group consisting of -(CH 2 )i -5 C(O)-Val-Ala-NH-(p-C6H 4 )-CH 2 OC(O)-(p-C 6 H 4 )-NO 2 , -(CH 2 CH 2 O)i-i 2 - (CH 2 CH 2 )C(O)-Val-Ala-NH-(p-C 6 H 4 )-CH 2 OC(O)-(p-C 6 H 4 )-NO 2 , -(CH 2 )i -5 C(O)-Val-Cit- NH-(p-C 6 H 4 )-CH 2 OC(O)-(p-C 6 H 4 )-NO 2 , -(CHsCHsOJi ⁇ -iCHsC ⁇ CiOJ-Val-Cit-NH-ip- C6
  • cytotoxins for use in conjugation to the linkers or ADCs disclosed herein.
  • chemotherapeutic agents for use in conjugation to the linkers or ADCs disclosed herein.
  • chemotherapeutic agents for example, in Chu, E., DeVite, V. T., 2012, Physicians' Cancer Chemotherapy Drug Manual 2012 (Jones & Bartlett Learning Oncology), and similar documents.
  • the cytotoxin may be any FDA-approved chemotherapeutic agent.
  • the CTX may be any FDA-approved chemotherapeutic agent available for cancer treatment.
  • the CTX is selected from the group consisting of an alkylating agent, an anthracycline, a cytoskeletal disruptor (taxane), an epothilone, an histone deacetylase Inhibitor (HDAC), an inhibitor of Topoisomerase I, an Inhibitor of Topoisomerase II, a kinase inhibitor, a monoclonal antibody, a nucleotide analog, a peptide antibiotic, a platinum-based agent, a retinoid, a Vinca alkaloid or a derivative thereof, and a radioisotope.
  • an alkylating agent an anthracycline
  • a cytoskeletal disruptor taxane
  • HDAC histone deacetylase Inhibitor
  • the CTX is selected from the group consisting of: thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine,
  • HYCAMTIN® CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); podophyllotoxin; podophyllinic acid;
  • teniposide teniposide
  • cryptophycins particularly cryptophycin 1 and cryptophycin 8
  • dolastatin duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics ⁇ e.g., calicheamicin, especially calicheamicin
  • dynemicin including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idar
  • lonidainine lonidainine
  • maytansinoids such as maytansine and ansamitocins
  • mitoguazone lonidainine
  • mitoxantrone mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid;
  • triaziquone 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C”); thiotepa; taxoids, e.g., TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANETM Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, III.), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; gemcitabine (GEMZAR
  • ifosfamide mitoxantrone; vincristine (ONCOVIN®); oxaliplatin; leucovovin; vinorelbine (NAVELBINE®); novantrone; edatrexate; daunomycin; aminopterin; ibandronate;
  • topoisomerase inhibitor RFS 2000 difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine (XELODA®); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovovin.
  • ELOXATINTM oxaliplatin
  • the CTX is selected from the group consisting of: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)- imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN®
  • SERMs selective estrogen receptor modulators
  • anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog);
  • protein kinase inhibitors such as ME inhibitors (WO 2007/044515);
  • lipid kinase inhibitors such as antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, for example, PKC-alpha, Raf and H- Ras, such as oblimersen (GENASENSE®, Genta Inc.);
  • ribozymes such as VEGF expression inhibitors ⁇ e.g., ANGIOZYME®) and HER2 expression inhibitors;
  • vaccines such as
  • LURTOTECAN® LURTOTECAN®; ABARELIX® rmRH; and (ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the above of.
  • the CTX is selected from the group consisting of: alkylating agents such as chlorambucil, bendamustine hydrochloride or
  • cyclophosphamide CYTOXAN®
  • purine analogs such as fludurabine (FLUDARA®), pentostatin (NIPENT®), cladribine or nelarabine
  • pyrimidine analogs such as cytarabine
  • corticosteroids such as prednisone, prednisolone or methylprednisolone
  • immunomodulatory agents such as lenalidomide or thalidomide, synthetic fl arms such as flavopiridol, Bcl2 antagonists such as oblimersen or ABT-263, antibiotics such as doxorubicin (ADRIAMYCIN®), daunorubicin, idarubicin, or mitoxentrone; antimetabolites such as methotrexate and clofarabine; tyrosine kinase inhibitors such as imatinib mesylate (GLEEVEC®), bosutinib, dasatinib, and nilotinib; a hypomethylating agents such as azacytidine or decitabine, an FLT3 inhibitor such as midostaurin, sorafenib, or AC220; arsenic trioxide; all-trans retinoic acid; vincristine sulfate; and monoclonal antibodies such as rituximab (RITUXAN
  • Chemotherapeutic agents may also include agents used in the treatment of multiple myeloma, including thalidomide, lenalidomide, bortezomib, dexamethesone, prednisone, and melphalan, as well as combinations of two or more of the above, such as thalidomide or lenalidomide plus dexamethasone, or bortezomib or lenalidomide plus melphalan and prednisone.
  • agents used in the treatment of multiple myeloma including thalidomide, lenalidomide, bortezomib, dexamethesone, prednisone, and melphalan, as well as combinations of two or more of the above, such as thalidomide or lenalidomide plus dexamethasone, or bortezomib or lenalidomide plus melphalan and prednisone.
  • the CTX is selected from the group consisting of Actinomycin, all-trans retinoic acid, Azacitidine, Azathioprine, Bleomycin, Bortezomib, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothilone, Etoposide, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, Irinotecan,
  • the CTX is selected from the group consisting of a tubulin stabilizer, a tubulin destabilizer, a DNA alkylator, a DNA minor groove binder, a DNA intercalator, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a gyrase inhibitor, a protein synthesis inhibitor, a proteosome inhibitor, and an anti-metabolite.
  • the CTX is selected from the group consisting of Actinomycin D, Amonafide, an auristatin, benzophenone, benzothiazole, a calicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin, Colchicine, Combretastatin A4, Dolastatin,
  • the CTX is an auristatin, a calicheamicin, a maytansinoid, or a tubulysin.
  • the CTX is monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), a pyrrolobenzodiazepine (PDB), calicheamicin ⁇ , mertansine, or tubulysin T2.
  • MMAE monomethylauristatin E
  • MMAF monomethylauristatin F
  • PDB pyrrolobenzodiazepine
  • calicheamicin ⁇ mertansine
  • tubulysin T2 tubulysin T2
  • the CTX is MMAE or MMAF.
  • the CTX is a PDB.
  • the CTX is
  • tubulysin T2 tubulysin T2
  • CTX tubulysin T3 or tubulysin T4, the structures for which are provided below:
  • CTX Cytotoxin
  • CTX is of the formula:
  • i 0 or 1
  • R 4 is a d-6 alkyl
  • R 5 is a C 1-6 alkyl
  • R 6 is C 1-6 alkyl
  • R 7 is selected from the group consisting of C 1-6 alkyl, -OC 1-6 alkyl,
  • R 8 is selected from the group consisting of -OH, -OC 1-6 alkyl, -CO 2 C 1-6 alkyl, -CO 2 C 6- ioaryl, -CH(C 1-6 alkyl)CO 2 R c , -CH(C 6- ioaryl)CO 2 R c , -NH-CH(C 5 H 6 ) 2 , -NHC 1-6 alkyl, -NH(CH 2 ) 3 -CO 2 R c , -NH(CH 2 CH 2 ) 2 C 6- i 0 aryl,
  • each R c is independently H or C 1-6 alkyl
  • R 17 is selected from the group consisting of H, -CH 3 and -C(O)CH 3 .
  • CTX is of the formula:
  • i 0 or 1
  • R 4 is a C 1-6 alkyl
  • R 5 is a C 1-6 alkyl
  • R 6 is selected from the group consisting of C 1-6 alkyl, C6-ioaryl
  • R 7 is selected from the group consisting of C 1-6 alkyl, -OC 1-6 alkyl,
  • R 8 is selected from the group consisting of -OH, -OC 1-6 alkyl, -CO 2 C 1-6 alkyl, -CO 2 C 6- ioaryl, -CH(C 1-6 alkyl)CO 2 R c , -CH(C 6- ioaryl)CO2R c , -NH-CH(C 5 H 6 ) 2 , -NHC 1-6 alkyl, -NH(CH 2 )3-CO 2 R c , -NH(CH 2 CH 2 ) 2 C 6- ioaryl,
  • each R c is independently selected from the group consisting of H, C 1-6 alkyl and C6-ioaryl;
  • R 17 is selected from the group consisting of H, -CH 3 and -C(O)CH 3 .
  • CTX is of the formula:
  • i 0 or 1
  • R 4 is a C 1-6 alkyl or C6-ioaryl
  • R 5 is a C 1-6 alkyl or C 6- ioaryl
  • R 6 is selected from the group consisting of C 1-6 alkyl, C6-ioaryl,
  • R 7 is selected from the group consisting of C 1-6 alkyl, -OC 1-6 alkyl,
  • R 8 is selected from the group consisting of -OH, -OC 1-6 alkyl, -CO 2 C 1-6 alkyl, -CO 2 C 6- i 0 aryl, -CH(C 1-6 alkyl)CO 2 R c , -CH(C 6- i 0 aryl)CO 2 R c , -NH-CH(C 5 H 6 ) 2 ,
  • each R c is independently selected from the group consisting of H, C 1-6 alkyl and C-6-ioaryl;
  • R 17 is selected from the group consisting of H, -CH 3 and -C(O)CH 3 .
  • the CTX is of the formula:
  • i 0 or 1
  • R 4 is a C 1-6 alkyl or C-6-ioaryl
  • R 5 is a C 1-6 alkyl or C-6-ioaryl
  • R 6 is selected from the group consisting of C 1-6 alkyl, C6-ioaryl,
  • R 7 is a bond to the linker L 1 , L 2 and/or L 3 ;
  • R 8 is selected from the group consisting of -OH, -OC 1-6 alkyl, -CO 2 C 1-6 alkyl, -CO 2 C 6- i 0 aryl, -CH(C 1-6 alkyl)CO 2 R c , -CH(C 6- i 0 aryl)CO 2 R c , -NH- CH(C 5 H 6 ) 2 , -NHC 1-6 alkyl, -NH(CH 2 ) 3 -CO 2 R c , -NH(CH 2 CH 2 ) 2 C 6- ioaryl,
  • the CTX is bonded to the linker from both at the squiggly line ( ⁇ ) and at the bond that is R 7 ; or the CTX is bonded to the linker only from the bond that is R 7 and not on the squiggly line bond at the amine nitrogen of the CTX of Formula CTX-III.
  • the CTX is of the formula CTX-llla:
  • R 4 is a C 1-6 alkyl
  • R 5 is a C 1-3 alkyl
  • R 6 is selected from the group consisting of C h alkyl, -CH 2 OCOC 1- 3alkyl, -CH 2 CO 2 C 1-3 alkyl, -CH 2 CONHC 1-3 alkyl, -CH(C 1-3 alkyl)CO 2 H and
  • R 7 is selected from the group consisting of -OC 1-3 alkyl, -NHC(O)C 1-3 alkyl, -OC(O)C 1-3 alkyl, -OC(O)-phenyl, -OC(O)NHC 1-6 alkyl and -OC(O)NHC 6- i 0 aryl; and
  • R 8 is selected from the group consisting of -NH(CH 2 CH 2 ) 2 -phenyl,
  • the CTX is of the formula CTX-llla:
  • R 4 is a C 1-6 alkyl
  • R 5 is a C 1-3 alkyl
  • R 6 is selected from the group consisting of C 1-3 alkyl, -CH 2 CO 2 C 1-3 alkyl and -CH(C 1-3 alkyl)CO 2 C 1-3 alkyl;
  • R 7 is selected from the group consisting of -OC 1-3 alkyl, -NHC(O)C 1-3 alkyl, -OC(O)C 1-3 alkyl, -OC(O)-phenyl, -OC(O)NHC 1-6 alkyl and -OC(O)NHC 6- i 0 aryl; and
  • R 8 is selected from the group consisting of -NH(CH 2 CH 2 ) 2 -phenyl,
  • CTX-I, CTX-II, CTX-llla, or CTX-lllb the CTX is not T3 or T4.
  • the CTX is of the formula:
  • R 4 is a C 1-6 alkyl or C 6- ioaryl
  • R 5 is a C 1-6 alkyl or C 6- ioaryl
  • R 6 is selected from the group consisting of C 1-6 alkyl, C6-ioaryl,
  • R 7 is selected from the group consisting of halo, C 1-6 alkyl, -OC 1-6 alkyl,
  • R 7 is a bond to the linker L 1 , L 2 and/or L 3 ;
  • R 8 is selected from the group consisting of -OH, -OC 1-6 alkyl
  • each R c is independently selected from the group consisting of H, C 1-6 alkyl and C 6- ioaryl;
  • R 18 is selected from the group consisting of H, -CH 3 and -C(O)CH 3 .
  • the CTX is of the formula CTX-IV or CTX-IVa: wherein: R 4 is a C 1-6 alkyl; R 5 is a C 1-6 alkyl;
  • R 6 is selected from the group consisting of C 1-3 alkyl, -CH 2 OCOC 1-3 alkyl, -CH 2 CO 2 C 1-3 alkyl, -CH 2 CONHC 1-3 alkyl and -CH(C 1-6 alkyl)CO 2 C 1-3 alkyl;
  • R 7 is selected from the group consisting of C 1-6 alkyl, -OC 1-6 alkyl,
  • R 8 is selected from the group consisting of -NH-CH(C 5 H 6 ) 2 , -NHC 1-6 alkyl, -NH(CH 2 ) 3 -CO 2 R c , -NH(CH 2 CH 2 ) 2 -phenyl, -NHCH(CH 2 -phenyl)CH 2 CH(CH 3 )CO 2 R c , -NHCH(CO 2 R c )CH 2 -phenyl, -NHCH(CH 2 CO 2 R c )CH 2 -phenyl and -NHCH(CO 2 R c )CH 2 - p-C6H -NHC 1-3 alkyl; wherein each R c is independently selected from the group consisting of H and C 1-3 alkyl.
  • the CTX is of the formula CTX-IV or CTX-IVa: wherein: R 4 is a C 1-6 alkyl; R 5 is a C 1-6 alkyl; R 6 is C 1-3 alkyl;
  • R 7 is selected from the group consisting of C 1-6 alkyl, -OC 1-6 alkyl and
  • R 8 is selected from the group consisting of -NH-CH(C 5 H 6 ) 2 , -NH(CH 2 CH 2 ) 2 - phenyl, -NHCH(CO 2 R c )CH 2 -phenyl and -NHCH(CO 2 R c )CH 2 -p-C 6 H 4 -NHC 1-3 alkyl; wherein each R c is independently selected from the group consisting of H and C 1-3 alkyl.
  • the CTX is of the formula:
  • R 4 is a C 1-6 alkyl or C6-ioaryl
  • R 5 is a C 1-6 alkyl or C6-ioaryl
  • R 6 is H or is selected from the group consisting of C 1-6 alkyl, C-6-ioaryl,
  • R 9 is selected from the group consisting C 1-6 alkyl, -phenyl, 1-naphthyl and 2- napthyl, wherein each -phenyl, 1-naphthyl and 2-naphthyl group is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of halo, cyano, nitro, CF 3 -, CF 3 O-, CH 3 O-, -C(O)CH 3 , -NH 2 , -OH, -SH, -NHCH 3 , -N(CH 3 ) 2 , -SMe and C 1-3 alkyl; and
  • R 10 is selected from the group consisting of C 1-3 alkyl, C 2-6 alkenyl, -O-C 1-3 alkyl and -OC6-ioaryl;
  • R 11 is H or C 1-3 alkyl
  • R c is selected from the group consisting of H, C h alkyl and C6-ioaryl
  • the CTX is of the formula CTX-V or CTX-Va: wherein: R 4 is a C 1-3 alkyl; R 5 is a C 1-3 alkyl;
  • R 6 is selected from the group consisting of C 1-3 alkyl, -CH 2 OCOC 1-3 alkyl, -CH 2 CO 2 C 1-3 alkyl, -CO 2 C 1-3 alkyl and -CH(C 1-3 alkyl)CO 2 C 1-3 alkyl;
  • R 9 is selected from the group consisting C 1-6 alkyl, -phenyl, 1-naphthyl and 2- napthyl, wherein each -phenyl, 1-naphthyl and 2-naphthyl is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of CF 3 -, CH 3 O-, -C(O)CH 3 , -NHCH 3 , -N(CH 3 ) 2 and C 1-3 alkyl; and
  • R 10 is selected from the group consisting of C 1-3 alkyl, C 2-6 alkenyl, -O-C 1-3 alkyl and -O-phenyl;
  • R 17 is selected from the group consisting of H, -CH 3 and -C(O)CH 3 .
  • the CTX is of the formula CTX-V: wherein: R 4 is a C h alkyl; R 5 is a C h alkyl; R 6 is C h alkyl;
  • R 9 is selected from the group consisting C 1-6 alkyl, -phenyl, 1-naphthyl and 2- napthyl;
  • R 10 is selected from the group consisting of C 1-3 alkyl and C 2-6 alkenyl.
  • CTX is of the formula:
  • each R 4 is independently a C 1-6 alkyl or C-6-ioaryl
  • R 5 is a C 1-6 alkyl or C 6- ioaryl
  • each R 6 is independently selected from the group consisting of H, C 1-6 alkyl, C 6- ioaryl, -CH 2 OCOC 1-6 alkyl, -CH 2 CO 2 C 1-6 alkyl, -CH 2 CONHC 1-6 alkyl, -CO 2 C 1-6 alkyl, -CH(C 1-6 alkyl)CO 2 H and -CH(C 1-6 alkyl)CO 2 C 1-6 alkyl;
  • each R 7 is independently selected from the group consisting of -CN, -OCi_ 6 alkyl, C 1-6 alkyl, -NHC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 6- i 0 aryl,
  • R 11 is H or C 1-3 alkyl
  • each R 12 is independently selected from the group consisting of halo, cyano, nitro, CF 3 -, CF 3 O-, CH 3 O-, -CO 2 H, -NH 2 , -OH, -SH, -NHCH 3 , -N(CH 3 ) 2 , -SMe, C 1-3 alkyl and C6-ioaryl;
  • R 13 is H or is selected from the group consisting of C 1-3 alkyl, -CF 3 , -C 1-3 alkyl- phenyl and C 6- ioaryl;
  • R 18 is selected from the group consisting of H, -CH 3 and -C(O)CH 3 ; and q is 0, 1 or 2.
  • the CTX is of the formula CTX-VI or CTX-VIa: wherein: each R 4 is independently a C h alkyl; R 5 is a C h alkyl;
  • each R 6 is independently selected from the group consisting of H, C 1-6 alkyl, -CH 2 OCOC 1-6 alkyl, -CH 2 C0 2 Ci.3alkyl > -CH(C 1-3 alkyl)CO 2 H and
  • each R 7 is independently selected from the group consisting of -OC 1-3 alkyl, C 1-3 alkyl, -NHC(O)C 1-3 alkyl, -OC(O)C 1-3 alkyl and -OC(O)C 6- i 0 aryl;
  • R 11 is H or C 1-3 alkyl
  • each R 12 is independently selected from the group consisting of halo, CF 3 -, CF 3 O-, CH 3 O-, -NHCH 3 , -N(CH 3 ) 2 , and C 1-3 alkyl;
  • R 13 is H or is selected from the group consisting of C 1-3 alkyl, -CF 3 , -C 1-3 alkyl- phenyl.
  • the CTX is of the formula CTX-VI:
  • each R 4 is independently a C 1-3 alkyl
  • R 5 is a C 1-3 alkyl
  • each R 6 is independently H or C 1-6 alkyl ;
  • each R 7 is independently selected from the group consisting of -OC 1-3 alkyl, -OC(O)C 1-3 alkyl, -OC(O)C 6- i 0 aryl, -OC(O)NHC 1-6 alkyl and -OC(O)NHC 6- i 0 aryl;
  • R 11 is H or C 1-3 alkyl
  • each R 12 is independently selected from the group consisting of CF 3 O-, CH 3 O- and C 1-3 alkyl;
  • R 13 is H or is selected from the group consisting of C 1-3 alkyl, -CF 3 , -C 1-3 alkyl- phenyl.
  • the CTX is of the formula:
  • R 11 is H or C 1-3 alkyl
  • each R 12 is independently selected from the group consisting of halo, cyano, nitro, CF 3 -, CF 3 O-, CH 3 O-, -CO 2 H, -NH 2 , -OH, -SH, -NHCH 3 , -N(CH 3 ) 2 , -SMe, C 1- 3alkyl and C6-ioaryl;
  • R 13 is H or is selected from the group consisting of C 1-3 alkyl, -CF 3 , -C 1-2 alkyl- phenyl and C6-ioaryl;
  • q 0, 1 or 2.
  • the CTX is of the formula CTX-VII:
  • R 11 is H
  • R 12 is selected from the group consisting of CF 3 -, CF 3 O-, CH 3 O-, -CO 2 H, -NHCH 3 , -N(CH 3 ) 2 , -C 1-3 alkyl and phenyl;
  • R 13 is H or is selected from the group consisting of C h alkyl, -C 1-2 alkyl-phenyl and phenyl;
  • R 18 is selected from the group consisting of H, -CH 3 and -C(O)CH 3 ;
  • the CTX is of the formula CTX-VII:
  • R 11 is H
  • R 13 is H, C 1-3 alkyl or -C 1-2 alkyl-phenyl; and q is 0.
  • CTX is of the formula:
  • each R 4 is independently a C 1-6 alkyl or C 6- ioaryl
  • R 5 is a C 1-6 alkyl or C6-ioaryl
  • each R 6 is independently selected from the group consisting of H, C 1-6 alkyl, C 6 -ioaryl, -CH 2 OCOC 1-6 alkyl, -CH 2 CO 2 C 1-6 alkyl, -CH 2 CONHC 1-6 alkyl, -CO 2 C 1-6 alkyl, -CH(C 1-6 alkyl)CO 2 H and -CH(C 1-6 alkyl)CO 2 C 1-6 alkyl;
  • each R 7 is independently selected from the group consisting of -CN,
  • R 11 is H or C 1-3 alkyl
  • R 14 is selected from the group consisting of C h alkyl and C6-ioaryl
  • R 15 is H or is selected from the group consisting of -OH, NH 2 , -NHCH 3 , C 1- 3alkyl, -OC 1- 3alkyl and -OC 6 -ioaryl;
  • R 16 is selected from the group consisting of C 1-6 alkyl, C 6- ioaryl and heteroaryl; and R 18 is selected from the group consisting of H, -CH 3 and -C(O)CH 3 .
  • the CTX is of the formula CTX-VIII or
  • each R 4 is independently a C 1-3 alkyl
  • R 5 is a C 1-3 alkyl
  • each R 6 is independently selected from the group consisting of H, C 1-6 alkyl, -CH 2 OCOC 1-6 alkyl, -CH 2 CO 2 C 1-3 alkyl, -CH(C 1-3 alkyl)CO 2 H and
  • each R 7 is independently selected from the group consisting of -OC 1-3 alkyl, C 1-3 alkyl, -NHC(O)C 1-3 alkyl, -OC(O)C 1-3 alkyl, -OC(O)C 6- i 0 aryl, -OC(O)NHC 1-6 alkyl and -OC(O)NHC 6- ioaryl;
  • R 11 is H or C 1-3 alkyl
  • R 14 is C 1-3 alkyl
  • R 15 is H or is selected from the group consisting of -OH, NH 2 , -NHCH 3 and -OC 1-3 alkyl; and R lb is C 6 -ioaryl.
  • the CTX is of the formula CTX-VIII or
  • each R 4 is independently a C h alkyl;
  • R 5 is a C 1- 3alkyl;
  • each R 6 is independently H or C 1-6 alkyl
  • each R 7 is independently selected from the group consisting of -OC 1-3 alkyl, -OC(O)C 1-3 alkyl, -OC(O)C 6- i 0 aryl, -OC(O)NHC 1-6 alkyl and -OC(O)NHC 6 -i 0 aryl;
  • R 11 is H or C 1-3 alkyl
  • R 14 is C 1-3 alkyl
  • R 15 is selected from the group consisting of -OH, NH 2 and -NHCH 3 ;
  • R 16 is C 6 -ioaryl.
  • any designated aryl group such as a C-6-ioaryl
  • linker-cytotoxin conjugate of the following formula (II):
  • each X and X' is independently O, S, NH or NR 1 wherein R 1 is C 1-6 alkyl;
  • each Y and Y' is independently hydrogen or an electrophilic leaving group that reacts selectively with thiols, provided if one of Y and Y' is hydrogen, the other is the electrophilic leaving group;
  • W is -NH-, -N(R 1 )-, -CH 2 -, -CH 2 -NH-, -CH 2 -N(R 1 )-, -CH 2 CH 2 -, -CH(R 2 )-, or
  • R 1 and R 2 are independently C1-6 alkyl
  • CTX is a cytotoxin
  • R is any chemical group; or R is absent;
  • each L 1 , L 2 and L 3 is independently a linker selected from the group consisting of -O-, -C(O)-, -S-, -S(O)-, -S(O) 2 -, -NH-, -NCH 3 -, -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) p , -(CH 2 CH 2 O) p CH 2 CH 2 -, -CH 2 CH 2 -(CH 2 CH 2 O) p -, -OCH(CH 2 O-) 2
  • a, b and c are each independently an integer of 0, 1, 2 or 3, provided that at least one of a, b or c is 1 ;
  • each k and k' is independently an integer of 0 or 1 ;
  • each p is independently an integer of 1 to 14;
  • each q is independently an integer or 1 to 12;
  • n is an integer of 1 to 4.
  • each AA is independently an amino acid
  • each r is 1 to 12;
  • the bond represents a single or a double bond.
  • k and k' are both 1.
  • linker-cytotoxin conjugate of the following formula ( ⁇ ):
  • each X and X' is independently O, S, NH or NR 1 wherein R 1 is C1-6 alkyl;
  • each Y and Y' is independently hydrogen or an electrophilic leaving group that
  • W is -NH-, -N(R 1 )-, -CH 2 -, -CH 2 -NH-, -CH 2 -N(R 1 )-, -CH 2 CH 2 -, -CH(R 2 )-, or
  • R 1 and R 2 are independently C 1-6 alkyl
  • CTX is a cytotoxin
  • R is any chemical group, provided that R is not OH;
  • each L 1 , L 2 and L 3 is independently a linker selected from the group consisting of -O-, -C(O)-, -S-, -S(O)-, -S(O) 2 -, -NH-, -NCH 3 -, -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) p ,
  • a, b and c are each independently an integer of 0, 1, 2 or 3, provided that at least one of a, b or c is 1;
  • each p is independently an integer of 1 to 14;
  • each q is independently an integer or 1 to 12;
  • n is an integer of 1 to 4.
  • each AA is independently an amino acid
  • each r is 1 to 12; and the bond represents a single or a double bond.
  • the bond represents a single bond. In certain embodiments of the linker of formula (I) or ( ⁇ ), the bond represents a double bond.
  • m is 1.
  • X and X' are O.
  • W is -NH- or -N(R 1 )-, wherein R 1 is C 1-6 alkyl.
  • W is -NH- or -N(R 1 )-, wherein R 1 is C 1- 3 alkyl.
  • W is -CH 2 NH- or -CH 2 N(R 1 )-, wherein R 1 is C 1-6 alkyl.
  • W is -CH 2 NH- or -CH 2 N(R 1 )-, wherein R 1 is C 1-3 alkyl.
  • W is -CH 2 -, -CH 2 CH 2 -, -CH(R 2 )-, or -CH 2 CH(R 2 ), wherein R 2 is C 1-6 alkyl. In certain embodiments, W is -CH 2 -, -CH 2 CH 2 -, -CH(R 2 )-, or -CH 2 CH(R 2 ), wherein R 2 is C 1-3 alkyl.
  • X and X' are O, and W is -NH-.
  • each Y and Y' is independently hydrogen or an electrophilic leaving group that reacts selectively with thiol.
  • each Y and Y' is independently selected from the group consisting of a halo, a substituted thiol, and a substituted sulfonate. In certain embodiments, each Y and Y' is independently selected from the group consisting of chloro, bromo, fluoro, and iodo.
  • each Y and Y' is independently selected from an optionally substituted thiophenyl, an optionally substituted thionaphthyl, an optionally substitued thiopyridyl, an optionally substituted isoquinolinyl, and an optionally substituted phenylsulfonate.
  • the linker-cytotoxin conjugate of formula (II) or ( ⁇ ) when one or both of Y and Y' is a substituted thiol, the substituent is selected from the group consisting of C6-io aryl and C 6 - ⁇ heteroaryl .
  • the substituent is selected from the group consisting of C 1-6 alkyl optionally substituted with halo or hydroxyl; phenyl optionally substituted with halo, hydroxyl, carboxyl, C 1- 3alkoxycarbonyl, or C 1- 3alkyl; naphthyl optionally substituted with halo, hydroxyl, carboxyl,
  • linker-cytotoxin conjugate of formula (II) or ( ⁇ ) when one or both of Y and Y' is a substituted sulfonate, the substituent is selected from the group consisting of C 1-6 alkyl, C2-iocycloalkyl, C6-ioaryl, and C6-ioheteroaryl.
  • each Y and Y' is independently selected from the group consisting of:
  • RA is selected from the group consisting of hydroxyl, amino, nitro, cyano, chloro, bromo, fluoro, iodo, oxo, carboxyl, C 1-6 alkoxycarbonyl, C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy.
  • RA is selected from the group consisting of halo, CF 3 -, CF 3 O-, CH 3 O-, -C(O)OH, -C(O)OC 1-3 alkyl, -C(O)CH 3 , -CN, -NH 2 , -OH, -NHCH 3 , -N(CH 3 ) 2 and C 1-3 alkyl.
  • each Y and Y' is independently selected from the group consisting of:
  • R is selected from the group consisting of W, (L 1 ) a , (L 2 ) b , (L 3 ) c , Z, W-(L 1 ) a -(L 2 ) b - (L 3 ) c , (L 1 )a-(L 2 ) b -(L 3 ) c -Z, and W-(L 1 ) a -(L 2 ) b -(L 3 ) c -Z, as defined herein.
  • R is selected from the group consisting of W, (L 1 ) a , (L 2 ) b , (L 3 ) c , and W- (L 1 )a-(L 2 )b-(L 3 ) c .
  • R is selected from the group consisting of Z, (L 1 )a-(L 2 ) b -(L 3 ) c -Z, and W-(L 1 ) a -(L 2 ) b -(L 3 ) c -Z.
  • R is a detectable probe.
  • R is a fluorophore
  • R is a ligand ⁇ e.g., a ligand specific for a receptor on a tumor cell, such as a prostate specific membrane antigen, or a virally infected cell, such as an HIV infected cell).
  • R is bonded to the rest of the linker molecule via an amide, an
  • N-(C 1-6 alkyl)amide a carbamate, an N-(C 1-6 alkyl)carbamate, an amine, an
  • N-(C 1-6 alkyl)amine an ether, a thioether, an urea, an N-(C 1-6 alkyl)urea, or an N,N-di(C 1-6 alkyl)urea bond.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -OCH(CH 2 O-) 2 and -C(O)NCH 3 -; a, b and c are each independently 0, 1 or 2; and each p and q is independently 1 or 2.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of
  • a, b and c are each independently 0 or 1 ; and each p and r is independently 1, 2 or 3.
  • each AA is an amino acid selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val.
  • (AA) r is a single amino acid selected from the group consisting of Gly, Arg, Val, Ala, Cys, Gin, Leu, lie, Leu, Lys and Ser or their N-methylated analogues.
  • (AA) r is selected from the group consisting of Gly-Gly, Gly-Arg, Gly-Val, Gly-Ala, Gly-Cys, Gly-Gln, Gly-lle, Leu, Lys-Leu, Gly-Lys and Gly-Ser or their N-methylated analogues.
  • (AA) r is selected from the group consisting of Gly-Gly-Gly, Gly-Arg-Gly, Gly-Val-Gly, Gly-Ala-Gly, Gly- Cys-Gly, Gly-Gln-Gly, Gly-lle-Gly, Lys-Leu-Gly, Gly-Lys-Gly and Gly-Ser-Gly or their N- methylated analogues.
  • (AA) r is selected from the group consisting of Ala-Ala, Ala-Gly, Ala-Arg, Ala-Val, Ala-Ala, Ala-Cys, Ala-Gin, Ala-lie, Ala-Leu, Ala-Lys and Ala-Ser or their N-methylated analogues.
  • (AA) r is selected from the group consisting of Ala-Ala-Ala, Ala-Gly-ALa, Ala- Arg-Ala, Ala-Val-Ala, Ala-Ala-Ala, Ala-Cys-Ala, Ala-Gin-Ala, Ala-lle-Ala, Ala-Leu-Ala, Ala-Lys-Ala and Ala-Ser-Ala or their N-methylated analogues.
  • L 1 is -(CH 2 ) q -
  • L 2 is absent
  • L 3 is absent
  • the CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via an amide bond.
  • L 1 is -(CH 2 ) q -
  • L 2 is -(OCH 2 CH 2 ) p -
  • L 3 is absent
  • the CTX is bonded to (L 1 ) a -(L 2 ) b - (L 3 ) c via an amide bond.
  • L 1 is -(CH 2 CH 2 O) p -
  • L 2 is -(CH 2 ) q -
  • L 3 is absent
  • the CTX is bonded to (L 1 ) a -(L 2 ) b - (L 3 ) c via an amide bond.
  • each L 1 is independently selected from the group consisting of -(CH 2 CH 2 O) p CH 2 CH 2 - and -CH 2 CH 2 -(CH 2 CH 2 O) p -, L 2 is absent, L 3 is absent, and the CTX is bonded to (L 1 ) a - (L 2 ) b -(L 3 ) c via an amide bond.
  • each L 1 is independently selected from the group consisting of -(CH 2 ) q -, -(CH 2 CH 2 O) p , -(CH 2 CH 2 O) p CH 2 CH 2 -, -CH 2 CH 2 -(CH 2 CH 2 O) p -, and -C(O)-, L 2 is Val-Cit, L 3 is PAB, and the CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via an amide bond.
  • each L 1 is independently selected from the group consisting of -(CH 2 ) q -, -(CH 2 CH 2 O) p , -(CH 2 CH 2 O) p CH 2 CH 2 -, -CH 2 CH 2 -(CH 2 CH 2 O) p -, and -C(O)-, L 2 is Val-Cit, L 3 is PAB, and the CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via an amide bond.
  • each L 1 is independently selected from the group consisting of -(CH 2 ) q -, -(CH 2 CH 2 O) p , -(CH 2 CH 2 O) p CH 2 CH 2 -, -CH 2 CH 2 -(CH 2 CH 2 O) p -, and -C(O)-, L 2 is Val-Ala, L 3 is PAB, and the CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via an amide bond.
  • CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via an amide, an N-(C 1-6 alkyl)amide, a
  • CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via a group selected from -NHC(O)-,
  • linker-cytotoxin conjugate of formula (II) or ( CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via a bond selected from the group consisting of:
  • each R B is independently branched or unbranched Ci
  • the CTX is monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), a pyrrolobenzodiazepine (PDB), calicheamicin ⁇ , mertansine, or tubulysin T2.
  • MMAE monomethylauristatin E
  • MMAF monomethylauristatin F
  • PDB pyrrolobenzodiazepine
  • calicheamicin ⁇ mertansine
  • tubulysin T2 tubulysin
  • the CTX is a PDB. In certain embodiments, the CTX is tubulysin T2. In certain embodiments, the CTX is tubulysin T3 or
  • tubulysin T4 tubulysin T4.
  • antibodies or antibody fragments (A) for use in the ADCs disclosed herein.
  • A is an antibody or an antibody fragment. In certain embodiments, A is a monoclonal antibody or monoclonal antibody fragment.
  • the antibody (A) is a monoclonal antibody or a humanized antibody.
  • the antibody is specific to a cancer antigen.
  • the antibody employed in the ADC of the present application is selected from the group consisting of alemtuzumab, bevacizumab, cetuximab, ipilimumab, ofatumumab, anitumumab, rituximab, tositumomab, inotuzumab, glembatumumab, lovortuzumab, milatuzumab and trastuzumab.
  • ADC Antibody-Drug Conjugate
  • A is an antibody or antibody fragment
  • cysteine residues are from an opened cysteine-cysteine disulfide
  • each X and X' is independently O, S, NH or NR 1 wherein R 1 is C1-6 alkyl;
  • W is -NH-, -N(R 1 )-, -CH 2 -, -CH 2 -NH-, -CH 2 -N(R 1 )-, -CH 2 CH 2 -, -CH(R 2 )-, or
  • R 1 and R 2 are independently C 1-6 alkyl
  • CTX is a cytotoxin
  • R is any chemical group; or R is absent;
  • each L 1 , L 2 and L 3 is independently a linker selected from the group consisting of -O- -C(O)-, -S-, -S(O)-, -S(O) 2 -, -NH-, -NCHs-, -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) p , -(CH 2 CH 2 O) p CH 2 CH 2 -, -CH 2 CH 2 -(CH 2 CH 2 O) p -, -OCH(CH 2 O-) 2 ,
  • a, b and c are each independently an integer of 0, 1, 2 or 3, provided that at least one of a, b or c is 1 ;
  • each k and k' is independently an integer of 0 or 1 ;
  • each p is independently an integer of 1 to 14;
  • each q is independently an integer or 1 to 12;
  • each AA is independently an amino acid
  • each r is 1 to 12;
  • n is an integer of 1 to 4.
  • n is an integer of 1 to 4.
  • the bond represents a single or a double bond.
  • k and k' are both 1.
  • A is an antibody or antibody fragment
  • cysteine residues are from an opened cysteine-cysteine disulfide
  • each X and X' is independently O, S, NH or NR 1 wherein R 1 is C 1-6 alkyl; W is -NH-, -N(R 1 )-, -CH 2 -, -CH 2 -NH-, -CH 2 -N(R 1 )-, -CH 2 CH 2 -, -CH(R 2 )-, or
  • R 1 and R 2 are independently C 1-6 alkyl
  • CTX is a cytotoxin
  • R is any chemical group, provided that R is not OH;
  • each L 1 , L 2 and L 3 is independently a linker selected from the group consisting of -O-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -NH-, -NCH 3 -, -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO2-, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(0)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) p , -(CH 2 CH 2 O)pCH 2 CH 2 -, -CH 2 CH 2 -(CH 2 CH 2 O) p -, -OCH(CH 2 O-) 2 , -(AA)
  • a, b and c are each independently 0, 1, 2 or 3, provided that at least one of a, b or c is 1;
  • each p is independently an integer of 1 to 14;
  • each q is independently an integer or 1 to 12;
  • each AA is independently an amino acid
  • each r is 1 to 12;
  • n is an integer of 1 to 4.
  • n is an integer of 1 to 4.
  • the bond represents a single or a double bond.
  • the bond represents a single bond. In certain embodiments of the antibody-drug conjugate of formula (III) or ( ⁇ ), the bond represents a double bond.
  • m is 1.
  • X and X' are O.
  • W is -NH- or -N(R 1 )-, wherein R 1 is C 1-6 alkyl.
  • W is -NH- or -N(R 1 )-, wherein R 1 is C 1- 3 alkyl.
  • W is -CH 2 NH- or -CH 2 N(R 1 )-, wherein R 1 is C 1-6 alkyl.
  • W is -CH 2 NH- or -CH 2 N(R 1 )-, wherein R 1 is C 1-3 alkyl. In certain embodiments, W is -CH 2 -, -CH 2 CH 2 -, -CH(R 2 )-, or -CH 2 CH(R 2 ), wherein R 2 is C 1-6 alkyl. In certain embodiments, W is -CH 2 -, -CH 2 CH 2 -, -CH(R 2 )-, or -CH 2 CH(R 2 ), wherein R 2 is C 1-3 alkyl.
  • X and X' are O, and W is -NH-.
  • R is selected from the group consisting of W, (L 1 ) a , (L 2 ) b , (L 3 ) c , Z, W-(L 1 ) a - (L 2 )b-(L 3 ) c , (L 1 )a-(L 2 ) b -(L 3 ) c -Z, and W-(L 1 ) a -(L 2 ) b -(L 3 ) c -Z, as defined herein.
  • R is selected from the group consisting of W, (L 1 ) a , (L 2 ) b , (L 3 ) c , and W- (L 1 ) a -(L 2 ) b -(L 3 ) c .
  • R is selected from the group consisting of Z, (L 1 ) a -(L 2 ) b -(L 3 ) c -Z, and W-(L 1 ) a -(L 2 ) b -(L 3 ) c -Z.
  • R is selected from the group consisting of W-(L 1 ) a -(L 2 ) b -(L 3 ) c -(CTX) m .
  • R is a detectable probe.
  • R is a fluorophore, chromophore, radiolabel, enzyme, ligand, antibody or antibody fragment.
  • R is a ligand ⁇ e.g., a ligand specific for a receptor on a tumor cell, such as a prostate specific membrane antigen, or a virally infected cell, such as an HIV infected cell). .
  • R is bonded to the rest of the linker molecule via an amide, an
  • N-(C 1-6 alkyl)amide a carbamate, an N-(C 1-6 alkyl)carbamate, an amine, an
  • N-(C 1-6 alkyl)amine an ether, a thioether, an urea, an N-(C 1-6 alkyl)urea, or an
  • N,N-di(C 1-6 alkyl)urea bond N,N-di(C 1-6 alkyl)urea bond.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -C(O)NCH 3 -, -(CH 2 CH 2 O) p ,
  • a, b and c are each independently 0, 1 or 2; each p, q and r is independently 1, 2, 3 or 4; and n is an integer of 1 to 4.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -(CH 2 ) q -, -NH(CH 2 ) 2 NH-, -OC(O)-, -CO 2 -, NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -OCH(CH 2 O-) 2 and -C(O)NCH 3 -; a, b and c are each independently 0, 1 or 2; each p and q is independently 1 or 2; and n is an integer of 1 to 4.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of -NH(CH 2 ) 2 NH-, -NHCH 2 CH 2 C(O)-, -C(O)NHCH 2 CH 2 NH-, -NHCH 2 C(O)-, -NHC(O)-, -C(O)NH-, -NCH 3 C(O)-, -OCH(CH 2 O-) 2 and -C(O)NCH 3 -; a, b and c are each
  • n is an integer of 1 to 4.
  • each L 1 , L 2 and L 3 is independently selected from the group consisting of
  • a, b and c are each independently 0 or 1 ; each p and r is independently 1, 2 or 3; and n is an integer of 1 to 4.
  • each AA is an amino acid selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val .
  • (AA) r is a single amino acid selected from the group consisting of Gly, Arg, Val, Ala, Cys, Gin, Leu, lie, Leu, Lys and Ser or their N-methylated analogues.
  • (AA) r is selected from the group consisting of Gly-Gly, Gly-Arg, Gly-Val, Gly-Ala, Gly-Cys, Gly-Gln, Gly-lle, Leu, Lys-Leu, Gly-Lys and Gly-Ser or their N-methylated analogues.
  • (AA) r is selected from the group consisting of Gly-Gly-Gly, Gly-Arg-Gly, Gly-Val-Gly, Gly-Ala-Gly, Gly- Cys-Gly, Gly-Gln-Gly, Gly-lle-Gly, Lys-Leu-Gly, Gly-Lys-Gly and Gly-Ser-Gly or their N- methylated analogues.
  • (AA) r is selected from the group consisting of Ala-Ala, Ala-Gly, Ala-Arg, Ala-Val, Ala-Ala, Ala-Cys, Ala-Gin, Ala-lie, Ala-Leu, Ala-Lys and Ala-Ser or their N-methylated analogues.
  • (AA) r is selected from the group consisting of Ala-Ala-Ala, Ala-Gly-ALa, Ala- Arg-Ala, Ala-Val-Ala, Ala-Ala-Ala, Ala-Cys-Ala, Ala-Gin-Ala, Ala-lle-Ala, Ala-Leu-Ala, Ala-Lys-Ala and Ala-Ser-Ala or their N-methylated analogues.
  • CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via a group selected from -NHC(O)-,
  • CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via a bond selected from the group consisting of:
  • each R B is independently branched or unbranched C1-6 alkyl.
  • A is an antibody that is specific to a cancer antigen.
  • A is selected from the group consisting of alemtuzumab, anitumumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, glembatumumab, inotuzumab, ipilimumab, lovortumumab, milatuzumab, ofatumumab, rituximab, tositumomab, and trastuzumab.
  • the antibody-drug conjugate of formula (III) or CTX is selected from a from the group consisting of a tubulin stabilizer, a tubulin destabilizer, a DNA alkylator, a DNA minor groove binder, a DNA intercalator, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a gyrase inhibitor, a protein synthesis inhibitor, a proteosome inhibitor, and an anti-metabolite.
  • the CTX is selected from the group consisting of Actinomycin D,
  • Amonafide an auristatin, benzophenone, benzothiazole, a calicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin, Colchicine, Combretastatin A4, Dolastatin,
  • the CTX is an auristatin, a calicheamicin, a maytansinoid, or a tubulysin.
  • the CTX is monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), a pyrrolobenzodiazepine (PDB),
  • calicheamicin ⁇ calicheamicin ⁇ , mertansine, or tubulysin T2.
  • the CTX is MMAE or MMAF.
  • the CTX is a PDB.
  • the CTX is tubulysin T2.
  • the CTX is tubulysin T3 or tubulysin T4.
  • k, k a, b and c may be defined as follows:

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Abstract

L'invention porte sur des conjugués anticorps-médicament anticorps-cytotoxine, et sur des composés connexes, tels que des conjugués lieur-cytotoxine et les lieurs utilisés pour les élaborer ainsi que des intermédiaires pour leur synthèse. L'invention concerne également des compositions et des méthodes y compris des méthodes permettant de traiter les cancers.
PCT/US2014/041399 2013-06-06 2014-06-06 Nouveaux lieurs pour conjugués anticorps-médicament et composés connexes, compositions, et procédés d'utilisation WO2014197854A1 (fr)

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US14/895,893 US11229711B2 (en) 2013-06-06 2014-06-06 Linkers for antibody-drug conjugates and related compounds, compositions, and methods of use
US17/545,562 US20230109312A1 (en) 2013-06-06 2021-12-08 Novel linkers for antibody-drug conjugates and related compounds, compositions, and methods of use

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US201361832130P 2013-06-06 2013-06-06
US61/832,130 2013-06-06
USPCT/US2013/064147 2013-10-09
PCT/US2013/064147 WO2014059028A1 (fr) 2012-10-09 2013-10-09 Anticorps anti-c16orf54 et leurs méthodes d'utilisation
US201361891390P 2013-10-15 2013-10-15
US61/891,390 2013-10-15
US201461981154P 2014-04-17 2014-04-17
US61/981,154 2014-04-17

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